Substituted Phenethylamines with Serotoninergic and/or Norepinephrinergic Activity

ABSTRACT

Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and/or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, attention deficit hyperactivity disorder, fibromyalgia, irritable bowel syndrome, and/or premature ejaculation are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/566,197, filed Sep. 10, 2019, which is a continuation of U.S.application Ser. No. 14/559,520, filed Dec. 3, 2014, now U.S. Pat. No.10,421,710, which is a continuation of U.S. patent application Ser. No.12/048,012, filed Mar. 13, 2008, which claims the benefit of thepriority of U.S. Provisional Patent Application Nos. 60/895,049, filedMar. 15, 2007, and 60/944,399, filed Jun. 15, 2007, the disclosures ofwhich are hereby incorporated by reference as if written herein in theirentirety

FIELD

The present invention is directed to inhibitors of the uptake ofmonoamine neurotransmitters and pharmaceutically acceptable salts andprodrugs thereof, the chemical synthesis thereof, and the medical use ofsuch compounds for the treatment and/or management of psychotropicdisorders, anxiety disorder, generalized anxiety disorder, depression,post-traumatic stress disorder, obsessive-compulsive disorder, panicdisorder, hot flashes, senile dementia, migraine, hepatopulmonarysyndrome, chronic pain, nociceptive pain, neuropathic pain, painfuldiabetic retinopathy, bipolar depression, obstructive sleep apnea,psychiatric disorders, premenstrual dysphoric disorder, social phobia,social anxiety disorder, urinary incontinence, anorexia, bulimianervosa, obesity, ischemia, head injury, calcium overload in braincells, drug dependence, attention deficit hyperactivity disorder,fibromyalgia, irritable bowel syndrome, and/or premature ejaculation.

BACKGROUND

Venlafaxine (Effexor®)(1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol) is atherapeutic agent whose efficacy is hypothesized to act throughinhibition of serotonin reuptake and, potentially, norepinephrinereuptake in neuronal cells. Norepinephrine activity modulation ispurported to occur at higher doses of venlafaxine than those requiredfor serotonin activity modulation. Venlafaxine also has the potential tomodulate dopamine activity, though the interaction in vitro is weak andthe clinical relevance of this interaction is unknown. The drugsubstance is sold as a 50/50 racemic mixture of R- and S-enantiomers.

Venlafaxine is converted in vivo by oxidative and conjugativedegradation to multiple metabolites, at least 48 of which aredocumented. The major metabolic pathways include phase I metabolismleading to demethylation at the oxygen and/or nitrogen centers andcyclohexyl ring hydroxylation, as well as phase II metabolism includingglucuronidation of the hydroxylated metabolites. Because venlafaxine ismetabolized by polymorphically-expressed isozymes of cytochrome P₄₅₀including CYPs 2C19 and 2D6, and because it can act as an inhibitor ofCYP2D6, its application in polypharmacy is necessarily complex and haspotential for adverse events. These CYPs are involved in the metabolismof medications that are typically prescribed concurrently withvenlafaxine. This phenomenon increases inter-patient variability inresponse to polypharmacy. An example of the critical need forimprovement of venlafaxine is the observed interpatient variability in“poor metabolizers” having either defective CYP2D6 alleles or total lackof CYP2D6 expression. These patients fail to convert venlafaxine to itsequipotent metabolite, 0-desmethylvenlafaxine. Venlafaxine also suffersfrom a short half-life relative to the majority of serotonin reuptakeinhibitors. The half-life of venlafaxine in humans is ˜5 hours, whileits active metabolite has a T_(1/2) of ˜11 hours. As a consequence ofits 5-11 hour pharmacological half-life, those taking venlafaxine are atsignificant risk of SRI discontinuation symptoms if the drug is abruptlydiscontinued. Furthermore, in order to overcome its short half-life, thedrug must be taken 2 (BID) or 3 (TID) times a day. An extended releaseformulation of Venlafaxine is also available; however, it does notsignificantly increase the carryover of drug to the next day. Most otherserotonin reuptake inhibitors (SRIs) have half-lives ≥24 hours. Thehalf-life of the primary active metabolite, O-desmethylvenlafaxine(“ODV”), is longer than that of the parent compound; however, it isstill desirable and beneficial to increase the half-life of ODV.

SUMMARY OF THE INVENTION

Disclosed herein is a pharmaceutically acceptable acid addition salt ofa compound having structural formula I:

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄,R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, and R₂₇ areindependently selected from the group consisting of hydrogen anddeuterium; and at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄,R₂₅, R₂₆, and R₂₇ is deuterium.

Further disclosed herein is a compound having structural formula II:

wherein R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, R₃₄, R₃₅, R₃₆, R₃₇, R₃₈, R₃₉, R₄₀,R₄₁, R₄₂, R₄₃, R₄₄, R₄₅, R₄₆, R₄₇, R₄₈, R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄,R₅₅, R₅₆, and R₅₇ are independently selected from the group consistingof hydrogen and deuterium; at least one of R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃,R₃₄, R₃₅, R₃₆, R₃₇, R₃₈, R₃₉, R₄₀, R₄₁, R₄₂, R₄₃, R₄₄, R₄₅, R₄₆, R₄₇,R₄₈, R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, and R₅₇ is deuterium; and Xis a leaving group anion.

Further disclosed herein is a compound having structural formula III:

wherein R₅₈, R₅₉, R₆₀, R₆₁, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀,R₇₁, R₇₂, R₇₃, R₇₄, R₇₅, R₇₆, R₇₇, R₇₈, R₇₉, R₈₀, R₈₁, and R₈₂ areindependently selected from the group consisting of hydrogen anddeuterium; and at least one of R₅₈, R₅₉, R₆₀, R₆₁, R₆₂, R₆₃, R₆₄, R₆₅,R₆₆, R₆₇, R₆₈, R₆₉, R₇₀, R₇₁, R₇₂, R₇₃, R₇₄, R₇₅, R₇₆, R₇₇, R₇₈, R₇₉,R₈₀, R₈₁, and R₈₂ is deuterium.

Further disclosed herein is a compound having structural formula IV:

wherein R₈₃, R₈₄, R₈₅, R₈₆, R₈₇, R₈₈, R₈₉, R₉₀, R₉₁, R₉₂, R₉₃, R₉₄, R₉₅,R₉₆, R₉₇, R₉₈, R₉₉, R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, and R₁₀₇are independently selected from the group consisting of hydrogen anddeuterium; and at least one of R₈₃, R₈₄, R₈₅, R₈₆, R₈₇, R₈₈, R₈₉, R₉₀,R₉₁, R₉₂, R₉₃, R₉₄, R₉₅, R₉₆, R₉₇, R₉₈, R₉₉, R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃,R₁₀₄, R₁₀₅, R₁₀₆, and R₁₀₇ is deuterium.

Also disclosed herein are pharmaceutical compositions comprising atleast one compound as disclosed herein or a pharmaceutically acceptablesalt, solvate, or prodrug thereof; in combination with one or morepharmaceutically acceptable excipients or carriers.

Further disclosed herein is a method for treating, preventing, orameliorating one or more symptoms of a monoamine-mediated disorder,which comprises administering to a subject a therapeutically effectiveamount of at least one compound as disclosed herein or apharmaceutically acceptable salt, solvate, or prodrug thereof.

Additionally provided herein is a method for treating, preventing, orameliorating one or more symptoms of the following disorders, including,but not limited to: psychotropic disorders, anxiety disorders,generalized anxiety disorder, depression, post-traumatic stressdisorder, obsessive-compulsive disorder, panic disorder, hot flashes,senile dementia, migraine, hepatopulmonary syndrome, chronic pain,nociceptive pain, neuropathic pain, painful diabetic retinopathy,bipolar depression, obstructive sleep apnea, psychiatric disorders,premenstrual dysphoric disorder, social phobia, social anxiety disorder,urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, headinjury, calcium overload in brain cells, drug dependence, Gilles de laTourette syndrome, Shy Drager syndrome, vasomotor flushing, chronicfatigue syndrome, cognition enhancement, attention deficit hyperactivitydisorder, fibromyalgia, irritable bowel syndrome, and/or prematureejaculation, which comprises administering to a subject atherapeutically effective amount of at least one compound as disclosedherein or a pharmaceutically acceptable salt, solvate, or prodrugthereof.

Further, disclosed herein are methods of modulating a target selectedfrom the group consisting of a serotonin receptor, a norepinephrinereceptor, a serotonin transporter, and a norepinephrine transporter.

In another aspect are processes for preparing a compound havingstructural formula I as serotonin and/or norepinephrine receptor and/ortransporter modulators, or other pharmaceutically acceptable derivativessuch as prodrug derivatives, or individual isomers and mixture ofisomers or enantiomers thereof.

In another aspect are processes for preparing a pharmaceuticallyacceptable salt of a compound having structural formula I.

In another aspect are processes for preparing a compound havingstructural formula II.

In another aspect are processes for preparing a compound havingstructural formula III.

Additionally disclosed herein is the use of a compound having structuralformula II for the manufacture of a compound having structural formulaI.

Additionally disclosed herein is the use of a compound having structuralformula III for the manufacture of a compound having structural formulaI.

Also disclosed herein are articles of manufacture and kits containingcompounds as disclosed herein. By way of example only, a kit or articleof manufacture can include a container (such as a bottle) with a desiredamount of at least one compound (or pharmaceutical composition of acompound) as disclosed herein. Further, such a kit or article ofmanufacture can further include instructions for using said compound (orpharmaceutical composition of a compound) as disclosed herein. Theinstructions can be attached to the container, or can be included in apackage (such as a box or a plastic or foil bag) holding the container.

In another aspect is the use of at least one compound as disclosedherein in the manufacture of a medicament for treating a disorder in ananimal in which serotonin and/or norepinephrine receptors contribute tothe pathology and/or symptomology of the disorder. In a further oralternative embodiment, said disorder is, but is not limited to, apsychotropic disorder, anxiety disorder, generalized anxiety disorder,depression, post-traumatic stress disorder, obsessive-compulsivedisorder, panic disorder, hot flashes, senile dementia, migraine,hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathicpain, painful diabetic retinopathy, bipolar depression, obstructivesleep apnea, psychiatric disorders, premenstrual dysphoric disorder,social phobia, social anxiety disorder, urinary incontinence, anorexia,bulimia nervosa, obesity, ischemia, head injury, calcium overload inbrain cells, drug dependence, Gilles de la Tourette syndrome, Shy Dragersyndrome, vasomotor flushing, chronic fatigue syndrome, cognitionenhancement, attention deficit hyperactivity disorder, fibromyalgia,irritable bowel syndrome, and/or premature ejaculation.

It has been found that the hydrochloride salt Forms A-F of the compoundof formula I have high crystallinity, i.e., substantially free ofamorphous material. Such salts have the advantage that they provide morereproducible dosing results. The hydrochloride salt Forms A-F of thecompound of formula I are substantially hygroscopically stable, whichalleviates potential problems associated with weight changes of theactive ingredient during the manufacture of capsules or tablets. Thehydrochloride Forms A-F of the compound of formula I have the additionaladvantage that they have a low tendency for concentrated aqueoussolution to form viscous mixtures upon standing. The hydrochloride saltForms A-F of the compound of formula I have rapid kinetic aqueoussolubility which simplifies aqueous dosing and make them suitable forinjectable dosage forms. Furthermore, the hydrochloride salt Forms A-Fof the compound of formula I with enhanced solubility characteristicsfacilitate the dissolution of solid dosage forms in a timely manner. Allof these advantages are specifically described herein for all of thepharmaceutical dosage forms, treatment regimens and therapeutic usesdescribed herein form compounds of formula I.

The hydrochloride salt Forms A-F of the compound of formula I havegreater kinetic solubility than the free base of the compound of formulaI. Additionally, the hydrochloride salt Forms A-F of the compound offormula I are more stable in air and can be used without deliquescence.In one aspect are compounds of formula I which can be stored in air andused without deliquescence, including for periods of more than 1 week,more than 2 weeks, more than 1 month, more than 2 months, more than 3months and more than 6 months.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form A) which was preparedand isolated according to the process disclosed in Example 34.

FIG. 2 is an X-ray powder diffraction spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form B) which was preparedand isolated according to the process disclosed in Example 35.

FIG. 3 is an X-ray powder diffraction spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form C) which was preparedand isolated according to the process disclosed in Example 36.

FIG. 4 is an X-ray powder diffraction spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form D) which was preparedand isolated according to the process disclosed in Example 37.

FIG. 5 is an X-ray powder diffraction spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form E) which was preparedand isolated according to the process disclosed in Example 38.

FIG. 6 is an X-ray powder diffraction spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form F) which was preparedand isolated according to the process disclosed in Example 39.

FIG. 7 is a solid state infrared absorption spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form A) which was preparedand isolated according to the process disclosed in Example 34.

FIG. 8 is a solid state infrared absorption spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form B) which was preparedand isolated according to the process disclosed in Example 35.

FIG. 9 is a solid state infrared absorption spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form C) which was preparedand isolated according to the process disclosed in Example 36.

FIG. 10 is a solid state infrared absorption spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form D) which was preparedand isolated according to the process disclosed in Example 37.

FIG. 11 is a solid state infrared absorption spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form E) which was preparedand isolated according to the process disclosed in Example 38.

FIG. 12 is a solid state infrared absorption spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form F) which was preparedand isolated according to the process disclosed in Example 39.

FIG. 13 is a thermogravimetric analysis (TGA) ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form B) which was preparedand isolated according to the process disclosed in Example 35, heated at10° C./min from ambient temperature to approximately 700° C. and then inregular mode to 1000° C., in a nitrogen atmosphere (25 cc/min).

FIG. 14 is a thermogravimetric analysis (TGA) ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form C) which was preparedand isolated according to the process disclosed in Example 36, heated at10° C./min from ambient to approximately 700° C. and then in regularmode to 1000° C., in a nitrogen atmosphere (25 cc/min).

FIG. 15 is a thermogravimetric analysis (TGA) spectrum ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride, Form E) which was preparedand isolated according to the process disclosed in Example 38, heated at10° C./min from ambient to approximately 700° C. and then in regularmode to 1000° C., in a nitrogen atmosphere (25 cc/min).

INCORPORATION BY REFERENCE

All publications (including WO07064697A1 and US20070149622A1) andreferences cited herein, including those in the background section, areexpressly incorporated herein by reference in their entirety. However,with respect to any similar or identical terms found in both theincorporated publications or references and those explicitly put forthor defined in this document, then those terms definitions or meaningsexplicitly put forth in this document shall control in all respects.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below. Generally, the nomenclature used herein andthe laboratory procedures in organic chemistry, medicinal chemistry, andpharmacology described herein are those well known and commonly employedin the art. In the event that there is a plurality of definitions for aterm used herein, those in this section prevail unless stated otherwise.

As used herein, the singular forms “a,” “an,” and “the” may refer toplural articles unless specifically stated otherwise.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human, monkey, chimpanzee, gorilla, and the like),rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like),lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline,and the like. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman patient.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder; or one or more of the symptomsassociated with the disorder; or alleviating or eradicating the cause(s)of the disorder itself.

The terms “prevent,” “preventing,” and “prevention” refer to a method ofdelaying or precluding the onset of a disorder; and/or its attendantsymptoms, barring a subject from acquiring a disorder or reducing asubject's risk of acquiring a disorder.

The term “therapeutically effective amount” refers to the amount of acompound that, when administered, is sufficient to prevent developmentof, or alleviate to some extent, one or more of the symptoms of thedisorder being treated. The term “therapeutically effective amount” alsorefers to the amount of a compound that is sufficient to elicit thebiological or medical response of a cell, tissue, system, animal, orhuman that is being sought by a researcher, veterinarian, medicaldoctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial. Each component must be “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation. It must also be suitable for use in contact with the tissueor organ of humans and animals without excessive toxicity, irritation,allergic response, immunogenecity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition; Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition; Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004).

The term “deuterium enrichment” refers to the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat the specified position. Because the naturally occurring distributionof deuterium is about 0.0156%, deuterium enrichment at any position in acompound synthesized using non-enriched starting materials is about0.0156%. The deuterium enrichment can be determined using conventionalanalytical methods known to one of ordinary skill in the art, includingmass spectrometry and nuclear magnetic resonance spectroscopy.

The term “is/are deuterium,” when used to describe a given position in amolecule such as R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃,R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅ and R₂₆ orthe symbol “D,” when used to represent a given position in a drawing ofa molecular structure, means that the specified position is enrichedwith deuterium above the naturally occurring distribution of deuterium.In one embodiment deuterium enrichment is of no less than about 1%, inanother no less than about 5%, in another no less than about 10%, inanother no less than about 20%, in another no less than about 50%, inanother no less than about 70%, in another no less than about 80%, inanother no less than about 90%, and in another no less than about 98% ofdeuterium at the specified position.

The term “isotopic enrichment” refers to the percentage of incorporationof a less prevalent isotope of an element at a given position in amolecule in the place of the more prevalent isotope of the element.

The term “non-isotopically enriched” refers to a molecule in which thepercentages of the various isotopes are substantially the same as thenaturally occurring percentages.

The terms “substantially pure” and “substantially homogeneous” meansufficiently homogeneous to appear free of readily detectable impuritiesas determined by standard analytical methods used by one of ordinaryskill in the art, including, but not limited to, thin layerchromatography (TLC), gel electrophoresis, high performance liquidchromatography (HPLC), infrared spectroscopy (IR), gas chromatography(GC), Ultraviolet Spectroscopy (UV), nuclear magnetic resonance (NMR),atomic force spectroscopy and mass spectroscopy (MS); or sufficientlypure such that further purification would not detectably alter thephysical and chemical properties, or biological and pharmacologicalproperties, such as enzymatic and biological activities, of thesubstance. In certain embodiments, “substantially pure” or“substantially homogeneous” refers to a collection of molecules, whereinat least about 50%, at least about 70%, at least about 80%, at leastabout 90%, at least about 95%, at least about 98%, at least about 99%,or at least about 99.5% of the molecules are a single compound,including a racemic mixture or single stereoisomer thereof, asdetermined by standard analytical methods.

The term “about” or “approximately” means an acceptable error for aparticular value, which depends in part on how the value is measured ordetermined. In certain embodiments, “about” can mean 1 or more standarddeviations.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients or carriers, to a subjectfor treating, preventing, or ameliorating one or more symptoms of adisorder.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a disorder.

The term “disorder” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disease,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the body or of one of its parts thatimpairs normal functioning and is typically manifested by distinguishingsigns and symptoms.

The term “release controlling excipient” refers to an excipient whoseprimary function is to modify the duration or place of release of theactive substance from a dosage form as compared with a conventionalimmediate release dosage form.

The term “nonrelease controlling excipient” refers to an excipient whoseprimary function do not include modifying the duration or place ofrelease of the active substance from a dosage form as compared with aconventional immediate release dosage form.

The term “pharmaceutically acceptable acid addition salt” refers to asalt prepared by contacting a compound having a basic functional groupwith a pharmaceutically acceptable acid.

The term “SNRI,” and “serotonin and/or norepinephrine receptor and/ortransporter modulator” are interchangeable and refer to a compound thatcan act as an inhibitor, or an antagonist of a serotonin receptor and/ortransporter, and/or norepinephrine receptor and/or transporter.

The term “monoamine-mediated disorder” refers to a disorder that ischaracterized by abnormal serotonin and/or norepinephrine levels, andwhen the levels of these neurotransmitters are modified, leads to theamelioration of other abnormal biological processes. Amonoamine-mediated disorder may be completely or partially mediated byabnormal serotonin, and/or norepinephrine receptors and/or transporters.In particular, a monoamine-mediated disorder is one in which modulationof serotonin-norepinephrine reuptake activity results in some effect onthe underlying condition, disorder, or disease, e.g., administration ofan SNRI results in some improvement in at least some of the patientsbeing treated.

The term “halogen”, “halide” or “halo” includes fluorine, chlorine,bromine, and iodine.

The term “leaving group” (LG) refers to any atom (or group of atoms)that is stable in its anion or neutral form after it has been displacedby a nucleophile and as such would be obvious to one of ordinary skilland knowledge in the art. The definition of “leaving group” includes butis not limited to: water, methanol, ethanol, chloride, bromide, iodide,an alkyl sulfonate, for example methanesulfonate, ethane sulfonate andthe like, an arylsulfonate, for example benzenesulfonate, tolylsulfonateand the like, a perhaloalkanesulfonate, for exampletrifluoromethanesulfonate, trichloromethanesulfonate and the like, analkylcarboxylate, for example acetate and the like, aperhaloalkylcarboxylate, for example trifluoroacetate, trichloroacetateand the like, an arylcarboxylate, for example benzoate and the like, anN-hydroxyimide anion, for example N-hydroxymaleimide anion,N-hydroxysuccinimide anion, N-hydroxyphthalimide anion,N-hydroxysulfosuccinimide anion and the like.

The term “protecting group” or “removable protecting group” refers to agroup which, when bound to a functionality, such as the oxygen atom of ahydroxyl or carboxyl group, or the nitrogen atom of an amino group,prevents reactions from occurring at that functional group, and whichcan be removed by a conventional chemical or enzymatic step toreestablish the functional group (Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999).

In light of the purposes described in the present disclosure, allreferences to “alkyl” and “aryl” groups or any groups ordinarilycontaining C—H bonds may include partially or fully deuterated versionsas required to affect the improvements outlined herein.

When the notation R_(n)—R_((n+x)) is used to represent a span ofconsecutive R groups, what is mean is that all R groups between andincluding said R groups are comprised by said notation. For example,R₁-R₂₇ is equivalent to R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁,R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅,R₂₆, and R₂₇.

When the term “increased” is used to compare a certain effect orproperty of an isotopically enriched (e.g., deuterated) compound to acorresponding non-isotopically enriched compound, what is meant is thatsaid effect or property is increased by greater than about 5%, greaterthan about 10%, greater than about 20%, greater than about 30%, greaterthan about 40%, or by greater than about 50% as compared to thecorresponding non-isotopically enriched compound. Similarly, when theterm “decreased” is used to compare a certain effect or property of anisotopically enriched (e.g., deuterated) compound to a correspondingnon-isotopically enriched compound, what is meant is that said effect orproperty is decreased by greater than about 5%, greater than about 10%,greater than about 20%, greater than about 30%, greater than about 40%,or by greater than about 50% as compared to the correspondingnon-isotopically enriched compound.

Deuterium Kinetic Isotope Effect

In an attempt to eliminate foreign substances, such as therapeuticagents, from its circulation system, the animal body expresses variousenzymes, such as the cytochrome P₄₅₀ enzymes or CYPs, esterases,proteases, reductases, dehydrogenases, and monoamine oxidases, to reactwith and convert these foreign substances to more polar intermediates ormetabolites for renal excretion. Some of the most common metabolicreactions of pharmaceutical compounds involve the oxidation of acarbon-hydrogen (C—H) bond to either a carbon-oxygen (C—O) orcarbon-carbon (C—C) π-bond. The resultant metabolites may be stable orunstable under physiological conditions, and can have substantiallydifferent pharmacokinetic, pharmacodynamic, and acute and long-termtoxicity profiles relative to the parent compounds. For most drugs, suchoxidations are generally rapid and ultimately lead to administration ofmultiple or high daily doses.

The relationship between the activation energy and the rate of reactionmay be quantified by the Arrhenius equation, k=Ae^(−Eact/RT), whereE_(act) is the activation energy, T is temperature, R is the molar gasconstant, k is the rate constant for the reaction, and A (the frequencyfactor) is a constant specific to each reaction that depends on theprobability that the molecules will collide with the correctorientation. The Arrhenius equation states that the fraction ofmolecules that have enough energy to overcome an energy barrier, thatis, those with energy at least equal to the activation energy, dependsexponentially on the ratio of the activation energy to thermal energy(RT), the average amount of thermal energy that molecules possess at acertain temperature.

The transition state in a reaction is a short lived state (on the orderof 10⁻¹⁴ sec) along the reaction pathway during which the original bondshave stretched to their limit. By definition, the activation energyE_(act) for a reaction is the energy required to reach the transitionstate of that reaction. Reactions that involve multiple steps willnecessarily have a number of transition states, and in these instances,the activation energy for the reaction is equal to the energy differencebetween the reactants and the most unstable transition state. Once thetransition state is reached, the molecules can either revert, thusreforming the original reactants, or new bonds form giving rise to theproducts. This dichotomy is possible because both pathways, forward andreverse, result in the release of energy. A catalyst facilitates areaction process by lowering the activation energy leading to atransition state. Enzymes are examples of biological catalysts thatreduce the energy necessary to achieve a particular transition state.

A carbon-hydrogen bond is by nature a covalent chemical bond. Such abond forms when two atoms of similar electronegativity share some oftheir valence electrons, thereby creating a force that holds the atomstogether. This force or bond strength can be quantified and is expressedin units of energy, and as such, covalent bonds between various atomscan be classified according to how much energy must be applied to thebond in order to break the bond or separate the two atoms.

The bond strength is directly proportional to the absolute value of theground-state vibrational energy of the bond. This vibrational energy,which is also known as the zero-point vibrational energy, depends on themass of the atoms that form the bond. The absolute value of thezero-point vibrational energy increases as the mass of one or both ofthe atoms making the bond increases. Since deuterium (D) has twice themass of hydrogen (H), it follows that a C-D bond is stronger than thecorresponding C—H bond. Compounds with C-D bonds are frequentlyindefinitely stable in H₂O, and have been widely used for isotopicstudies. If a C—H bond is broken during a rate-determining step in achemical reaction (i.e. the step with the highest transition stateenergy), then substituting a deuterium for that hydrogen will cause adecrease in the reaction rate and the process will slow down. Thisphenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). Themagnitude of the DKIE can be expressed as the ratio between the rates ofa given reaction in which a C—H bond is broken, and the same reactionwhere deuterium is substituted for hydrogen. The DKIE can range fromabout 1 (no isotope effect) to very large numbers, such as 50 or more,meaning that the reaction can be fifty, or more, times slower whendeuterium is substituted for hydrogen. High DKIE values may be due inpart to a phenomenon known as tunneling, which is a consequence of theuncertainty principle. Tunneling is ascribed to the small mass of ahydrogen atom, and occurs because transition states involving a protoncan sometimes form in the absence of the required activation energy.Because deuterium has more mass than hydrogen, it statistically has amuch lower probability of undergoing this phenomenon. Substitution oftritium for hydrogen results in yet a stronger bond than deuterium andgives numerically larger isotope effects

Discovered in 1932 by Urey, deuterium (D) is a stable andnon-radioactive isotope of hydrogen. It was the first isotope to beseparated from its element in pure form and has twice the mass ofhydrogen, and makes up about 0.02% of the total mass of hydrogen (inthis usage meaning all hydrogen isotopes) on earth. When two deuteriumatoms bond with one oxygen, deuterium oxide (D₂O or “heavy water”) isformed. D₂O looks and tastes like H₂O, but has different physicalproperties. It boils at 101.41° C. and freezes at 3.79° C. Its heatcapacity, heat of fusion, heat of vaporization, and entropy are allhigher than H₂O. It is more viscous and has different solubilizingproperties than H₂O.

When pure D₂O is given to rodents, it is readily absorbed and reaches anequilibrium level that is usually about eighty percent of theconcentration of what was consumed. The quantity of deuterium requiredto induce toxicity is extremely high. When 0% to as much as 15% of thebody water has been replaced by D₂O, animals are healthy but are unableto gain weight as fast as the control (untreated) group. When about 15%to about 20% of the body water has been replaced with D₂O, the animalsbecome excitable. When about 20% to about 25% of the body water has beenreplaced with D₂O, the animals are so excitable that they go intofrequent convulsions when stimulated. Skin lesions, ulcers on the pawsand muzzles, and necrosis of the tails appear. The animals also becomevery aggressive; males becoming almost unmanageable. When about 30%, ofthe body water has been replaced with D₂O, the animals refuse to eat andbecome comatose. Their body weight drops sharply and their metabolicrates drop far below normal, with death occurring at about 30 to about35% replacement with D₂O. The effects are reversible unless more thanthirty percent of the previous body weight has been lost due to D₂O.Studies have also shown that the use of D₂O can delay the growth ofcancer cells and enhance the cytotoxicity of certain antineoplasticagents.

Tritium (T) is a radioactive isotope of hydrogen, used in research,fusion reactors, neutron generators and radiopharmaceuticals. Mixingtritium with a phosphor provides a continuous light source, a techniquethat is commonly used in wristwatches, compasses, rifle sights and exitsigns. It was discovered by Rutherford, Oliphant and Harteck in 1934,and is produced naturally in the upper atmosphere when cosmic rays reactwith H2 molecules. Tritium is a hydrogen atom that has 2 neutrons in thenucleus and has an atomic weight close to 3. It occurs naturally in theenvironment in very low concentrations, most commonly found as T₂O, acolorless and odorless liquid. Tritium decays slowly (half-life=12.3years) and emits a low energy beta particle that cannot penetrate theouter layer of human skin. Internal exposure is the main hazardassociated with this isotope, yet it must be ingested in large amountsto pose a significant health risk. As compared with deuterium, a lesseramount of tritium must be consumed before it reaches a hazardous level.

Deuteration of pharmaceuticals to improve pharmacokinetics (PK),pharmacodynamics (PD), and toxicity profiles, has been demonstratedpreviously with some classes of drugs. For example, the DKIE was used todecrease the hepatotoxicity of halothane by presumably limiting theproduction of reactive species such as trifluoroacetyl chloride.However, this method may not be applicable to all drug classes. Forexample, deuterium incorporation can lead to metabolic switching. Theconcept of metabolic switching asserts that xenogens, when sequesteredby Phase I enzymes, may bind transiently and re-bind in a variety ofconformations prior to the chemical reaction (e.g., oxidation). Thishypothesis is supported by the relatively vast size of binding pocketsin many Phase I enzymes and the promiscuous nature of many metabolicreactions. Metabolic switching can potentially lead to differentproportions of known metabolites as well as altogether new metabolites.This new metabolic profile may impart more or less toxicity. Suchpitfalls are non-obvious and are not predictable a priori for any drugclass.

Deuterated Phenethylamine Derivatives

Venlafaxine is a substituted phenethylamine-based SNRI. Thecarbon-hydrogen bonds of venlafaxine contain a naturally occurringdistribution of hydrogen isotopes, namely 1H or protium (about99.9844%), 2H or deuterium (about 0.0156%), and 3H or tritium (in therange between about 0.5 and 67 tritium atoms per 1018 protium atoms).Increased levels of deuterium incorporation may produce a detectableKinetic Isotope Effect (KIE) that could affect the pharmacokinetic,pharmacologic and/or toxicologic profiles of such SNRIs in comparisonwith the compound having naturally occurring levels of deuterium.

The novel approach to designing and synthesizing new analogs ofvenlafaxine and related compounds through incorporation of deuteriumdisclosed herein may generate novel monoamine reuptake inhibitors withunexpected and non-obvious improvements of pharmacological,pharmacokinetic and toxicological properties in comparison to thenon-isotopically enriched monoamine reuptake inhibitors.

Both N-methyl groups, the single O-methyl, and several sites on thecyclohexyl ring of venlafaxine are now known to be sites of cytochromeP₄₅₀ metabolism. The toxicities of all resultant metabolites are notknown. Furthermore, because polymorphically expressed CYPs such as 2C19and 2D6 oxidize venlafaxine, and because venlafaxine inhibits thepolymorphically expressed CYP2D6, the prevention of such interactionsdecreases interpatient variability, decreases drug-drug interactions,increases T_(1/2), decreases the necessary C_(max), and improves severalother ADMET parameters. For example, the half-life of venlafaxine rangesfrom 3-7 hours. The equipotent metabolite, 0-demethylated venlafaxine(ODV), has a half-life averaging 11 hours. Various deuteration patternscan be used to a) alter the ratio of active metabolites, b) reduce oreliminate unwanted metabolites, c) increase the half-life of the parentdrug, and/or d) increase the half-life of active metabolites and createa more effective drug and a safer drug for polypharmacy, whether thepolypharmacy be intentional or not. High doses of venlafaxine are oftenprescribed in order to reach levels capable of inhibiting norepinephrinereuptake. Unfortunately, high doses are also associated withhypertension. Since these phenomena are linked by the pharmaceuticalagent rather than the pharmacological target, they are theoreticallyseparable by increasing the half-life, thus allowing dosing in a rangethat lowers the C_(max) and thus may avoid triggering the mechanismleading to hypertension. Further illustrating this point, venlafaxine isknown to display linear kinetics at the low end of the dose range, 75mg/day, but displays non-linear kinetics at the high end of the doserange, ˜400 mg/day, as a result of the saturation of clearancemechanisms. This non-linearity produces an ascending, rather than aflat, dose-response curve for venlafaxine. The deuteration approach hasstrong potential to slow metabolism through the previously saturatedmechanism allowing linear, more predictable ADMET responses throughoutthe dose range (which would also be lower via this invention). Thisleads to lesser interpatient variability of the type that can lead tothe hypertensive effects.

The compounds disclosed herein have the potential to uniquely maintainthe beneficial aspects of the non-isotopically enriched drugs whilesubstantially increasing the half-life (T_(1/2)), lowering the maximumplasma concentration (C_(max)) of the minimum efficacious dose (MED),lowering the efficacious dose and thus decreasing thenon-mechanism-related toxicity, and/or lowering the probability ofdrug-drug interactions. These drugs also have strong potential to reducethe cost-of-goods (COG) owing to the ready availability of inexpensivesources of deuterated reagents combined with previously mentionedpotential for lowering the therapeutic dose. It has been discovered thatdeuteration at the N-methyl and the O-methyl groups alone, deuterationat the N-methyl and the O-methyl groups in combination, or deuterationof additional sites found to be labile as a result of metabolicswitching are effective in achieving some of the objectives disclosedherein.

In the following embodiments below, further embodiments of each areprovided, wherein each compound may be substantially a singleenantiomer, a mixture of about 90% or more by weight of the(−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, amixture of about 90% or more by weight of the (+)-enantiomer and about10% or less by weight of the (−)-enantiomer, substantially an individualdiastereomer, or a mixture of about 90% or more by weight of anindividual diastereomer and about 10% or less by weight of any otherdiastereomer.

Also in the following embodiments below, further embodiments of each areprovided, wherein at least one of each R group designated to bedeuterium independently has deuterium enrichment of no less than about1%, no less than about 5%, no less than about 10%, no less than about20%, no less than about 50%, no less than about 70%, no less than about80%, no less than about 90%, no less than about 95%, or no less thanabout 98%.

In one embodiment, disclosed herein is a pharmaceutically acceptableacid addition salt of a compound having structural formula I:

wherein R₁-R₂₇ are independently selected from the group consisting ofhydrogen and deuterium; and at least one of R₁-R₂₇ is deuterium.

In yet another embodiment, at least one of R₁, R₂, and R₃ is deuterium.

In yet another embodiment, R₁, R₂, and R₃ are deuterium.

In yet another embodiment, at least one of R₁₁, R₁₂, and R₁₃ isdeuterium.

In yet another embodiment, R₁₁, R₁₂, and R₁₃ are deuterium.

In yet another embodiment, at least one of R₁, R₂, R₃, R₁₁, R₁₂, and R₁₃is deuterium.

In yet another embodiment, R₁, R₂, R₃, R₁₁, R₁₂, and R₁₃ are deuterium.

In yet another embodiment, at least one of R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, andR₁₆ is deuterium.

In yet another embodiment, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆ aredeuterium.

In yet another embodiment, at least one of R₁, R₂, R₃, R₁₁, R₁₂, R₁₃,R₁₄, R₁₅, and R₁₆ is deuterium.

In yet another embodiment, R₁, R₂, R₃, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆are deuterium.

In yet another embodiment, at least one of R₁, R₂, and R₃ is deuterium;and R₄-R₂₇ are hydrogen.

In yet another embodiment, R₁, R₂, and R₃ are deuterium; and R₄-R₂₇ arehydrogen.

In yet another embodiment, at least one of R₁₁, R₁₂, and R₁₃ isdeuterium; and R₁, R₂, R₃, R₄-R₁₀, and R₁₄-R₂₇ are hydrogen.

In yet another embodiment, R₁₁, R₁₂, and R₁₃ are deuterium; and R₁, R₂,R₃, R₄-R₁₀, and R₁₄-R₂₇ are hydrogen.

In yet another embodiment, at least one of R₁, R₂, R₃, R₁₁, R₁₂, and R₁₃is deuterium; and R₄-R₁₀ and R₁₄-R₂₇ are hydrogen.

In yet another embodiment, R₁, R₂, R₃, R₁₁, R₁₂, and R₁₃ are deuterium;and R₄-R₁₀ and R₁₄-R₂₇ are hydrogen.

In yet another embodiment, at least one of R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, andR₁₆ is deuterium; and R₁-R₁₀ and R₁₇-R₂₇ are hydrogen.

In yet another embodiment, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆ aredeuterium; and R₁-R₁₀ and R₁₇-R₂₇ are hydrogen.

In yet another embodiment, at least one of R₁, R₂, R₃, R₁₁, R₁₂, R₁₃,R₁₄, R₁₅, and R₁₆ is deuterium; and R₄-R₁₀ and R₁₇-R₂₇ are hydrogen.

In yet another embodiment, R₁, R₂, R₃, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆are deuterium; and R₄-R₁₀ and R₁₇-R₂₇ are hydrogen.

In yet another embodiment, a pharmaceutically acceptable acid additionsalt of a compound has a structural formula selected from the groupconsisting of:

In one embodiment, disclosed herein is a compound having structuralformula II:

wherein R₂₈-R₅₇ are independently selected from the group consisting ofhydrogen and deuterium; at least one of R₂₈-R₅₇ is deuterium; and X is aleaving group anion.

In yet another embodiment, at least one of R₂₈, R₂₉, and R₃₀ isdeuterium.

In yet another embodiment, R₂₈, R₂₉, and R₃₀ are deuterium.

In yet another embodiment, at least one of R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄,R₅₅, R₅₆, and R₅₇ is deuterium.

In yet another embodiment, R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, andR₅₇ are deuterium.

In yet another embodiment, at least one of R₂₈, R₂₉, R₃₀, R₄₉, R₅₀, R₅₁,R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, and R₅₇ is deuterium.

In yet another embodiment, R₂₈, R₂₉, R₃₀, R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄,R₅₅, R₅₆, and R₅₇ are deuterium.

In yet another embodiment, at least one of R₂₈, R₂₉, and R₃₀ isdeuterium; and R₃₁-R₅₇ are hydrogen.

In yet another embodiment, R₂₈, R₂₉, and R₃₀ are deuterium; and R₃₁-R₅₇are hydrogen.

In yet another embodiment, at least one of R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄,R₅₅, R₅₆, and R₅₇ is deuterium; and R₂₈-R₄₈ are hydrogen.

In yet another embodiment, R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, andR₅₇ are deuterium; and R₂₈-R₄₈ are hydrogen.

In yet another embodiment, at least one of R₂₈, R₂₉, R₃₀, R₄₉, R₅₀, R₅₁,R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, and R₅₇ is deuterium; and R₃₁-R₄₈ are hydrogen.

In yet another embodiment, R₂₈, R₂₉, R₃₀, R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄,R₅₅, R₅₆, and R₅₇ are deuterium; and R₃₁-R₄₈ are hydrogen.

In one embodiment, X is selected from the group consisting of halogen,alkylsulfonate, arylsulfonate, perhaloalkanesulfonate, CH₃OSO₃ ⁻, andCD₃OSO₃ ⁻.

In another embodiment, X is iodide.

In yet another embodiment, a compound has a structural formula selectedfrom the group consisting of:

In one embodiment, disclosed herein is a compound having structuralformula III:

wherein R₅₈-R₈₂ are independently selected from the group consisting ofhydrogen and deuterium; and at least one of R₅₈-R₈₂ is deuterium.

In yet another embodiment, at least one of R₅₈, R₅₉, and R₆₀ isdeuterium.

In yet another embodiment, R₅₈, R₅₉, and R₆₀ are deuterium.

In yet another embodiment, at least one of R₆₈, R₆₉, R₇₀, R₈₁, and R₈₂is deuterium.

In yet another embodiment, R₆₈, R₆₉, R₇₀, R₈₁, and R₈₂ are deuterium.

In yet another embodiment, at least one of R₅₈, R₅₉, R₆₀, R₆₈, R₆₉, R₇₀,R₈₁, and R₈₂ is deuterium.

In yet another embodiment, R₅₈, R₅₉, R₆₀, R₆₈, R₆₉, R₇₀, R₈₁, and R₈₂are deuterium.

In yet another embodiment, at least one of R₅₈, R₅₉, and R₆₀ isdeuterium; and R₆₁-R₈₂ are hydrogen.

In yet another embodiment, R₅₈, R₅₉, and R₆₀ are deuterium; and R₆₁-R₈₂are hydrogen.

In yet another embodiment, at least one of R₆₈, R₆₉, R₇₀, R₈₁, and R₈₂is deuterium; and R₅₈-R₆₇ and R₇₀-R₇₉ are hydrogen.

In yet another embodiment, R₆₈, R₆₉, R₇₀, R₈₁, and R₈₂ are deuterium;and R₅₈-R₆₇ and R₁₀-R₇₉ are hydrogen.

In yet another embodiment, at least one of R₅₈, R₅₉, R₆₀, R₆₈, R₆₉, R₇₀,R₈₁, and R₈₂ is deuterium; and R₆₁-R₆₇ and R₇₀-R₇₉ are hydrogen.

In yet another embodiment, R₅₈, R₅₉, R₆₀, R₆₈, R₆₉, R₇₀, R₈₁, and R₈₂are deuterium; and R₆₁-R₆₇ and R₇₀-R₇₉ are hydrogen.

In yet another embodiment, a compound has a structural formula selectedfrom the group consisting of:

In one embodiment, disclosed herein is a compound having structuralformula IV:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof;wherein R₈₃-R₁₀₇ are independently selected from the group consisting ofhydrogen and deuterium; and at least one of R₈₃-R₁₀₇ is deuterium.

In yet another embodiment, at least one of R₁₀₂, R₁₀₃, and R₁₀₄ isdeuterium.

In yet another embodiment, R₁₀₂, R₁₀₃, and R₁₀₄ are deuterium.

In yet another embodiment, at least one of R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆,and R₁₀₇ is deuterium.

In yet another embodiment, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, and R₁₀₇ aredeuterium.

In yet another embodiment, at least one of R₁₀₀ and R₁₀₁ is deuterium.

In yet another embodiment, R₁₀₀ and R₁₀₁ are deuterium.

In yet another embodiment, at least one of R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃, andR₁₀₄ is deuterium.

In yet another embodiment, R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃, and R₁₀₄ aredeuterium.

In yet another embodiment, at least one of R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄,R₁₀₅, R₁₀₆, and R₁₀₇ is deuterium.

In yet another embodiment, R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, andR₁₀₇ are deuterium.

In yet another embodiment, at least one of R₁₀₂, R₁₀₃, and R₁₀₄ isdeuterium, and R₈₃-R₁₀₁, R₁₀₅, R₁₀₆, and R₁₀₇ are hydrogen.

In yet another embodiment, R₁₀₂, R₁₀₃, and R₁₀₄ are deuterium, andR₈₃-R₁₀₁, R₁₀₅, R₁₀₆, and R₁₀₇.

In yet another embodiment, at least one of R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆,and R₁₀₇ is deuterium, and R₈₃-R₁₀₁ are hydrogen.

In yet another embodiment, R₁₀₂, R₁₀₃, R₁₀₄, R₁₀₅, R₁₀₆, and R₁₀₇ aredeuterium, and R₈₃-R₁₀₁ are hydrogen.

In yet another embodiment, at least one of R₁₀₀ and R₁₀₁ is deuterium,and R₈₃-R₉₉ and R₁₀₂-R₁₀₇ are hydrogen.

In yet another embodiment, R₁₀₀ and R₁₀₁ are deuterium, and R₈₃-R₉₉ andR₁₀₂-R₁₀₇ are hydrogen.

In yet another embodiment, at least one of R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃, andR₁₀₄ is deuterium, and R₈₃-R₉₉, R₁₀₅, R₁₀₆, and R₁₀₇ are hydrogen.

In yet another embodiment, R₁₀₀, R₁₀₁, R₁₀₂, R₁₀₃, and R₁₀₄ aredeuterium, and R₈₃-R₉₉, R₁₀₅, R₁₀₆, and R₁₀₇ are hydrogen.

In yet another embodiment, at least one of R₁₀₀-R₁₀₇ is deuterium, andR₈₃-R₉₉ are hydrogen.

In yet another embodiment, R₁₀₀-R₁₀₇ are deuterium, and R₈₃-R₉₉ arehydrogen.

In yet another embodiment, a compound has a structural formula selectedfrom the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In yet another embodiment, a compound has the structural formula:

-   -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In a further embodiment, said compound contains about 50% or more byweight of the (−)-enantiomer of said compound and about 50% or less byweight of (+)-enantiomer of said compound or about 50% or more by weightof the (+)-enantiomer of said compound and about 50% or less by weightof (−)-enantiomer of said compound.

In another aspect are processes for preparing a compound havingstructural formula I as serotonin and/or norepinephrine receptor and/ortransporter modulators, or other pharmaceutically acceptable derivativessuch as prodrug derivatives, or individual isomers and mixture ofisomers or enantiomers thereof.

In another embodiment are disclosed processes for preparing a compoundhaving structural formula II, or individual isomers and mixture ofisomers or enantiomers thereof.

In another embodiment is provided the use of a compound havingstructural formula II for the manufacture of a compound havingstructural formula I.

In one embodiment, disclosed herein is a process for preparing acompound having structural formula I wherein R₁-R₂₇ are independentlyselected from the group consisting of hydrogen and deuterium. Such aprocess can be performed, for example, by reacting a compound havingstructural formula II, wherein R₂₈-R₅₇ are independently selected fromthe group consisting of hydrogen and deuterium, and X is a leaving groupanion, under conditions suitable to form a compound having structuralformula I, as set forth below:

Compounds having structural formula II can be prepared by methods knownto one of skill in the art or following procedures similar to thosedescribed in the Example section herein and routine modificationsthereof. Compound II is contacted with a nucleophile at an elevatedtemperature. Nucleophiles contemplated for use in the practice of thisparticular disclosure include, but are not limited to, 2-aminoethanol,3-aminopropanol, 1,8-diazabicyclo[5.4.0]undec-7ene,1,4-diazabicyclo[2.2.2]octane, trialkylamine, sodium borohydride,lithium borohydride, lithium trialkylborohydride, lithium hydride,potassium hydride, and sodium hydride. Solvents contemplated for use inthe practice of this particular disclosure include, but are not limitedto, polar solvents such as 1,4-dioxane, acetone, acetonitrile,dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or suitable mixtures thereof. The process is carried out at atemperature from about 0° C. to about 500° C., for about 0.01 to about240 hours, at a pH from about 1 to about 14, at a pressure from about 1mBar to about 350 Bar.

In certain embodiments, compounds having structural formula II arecontacted with a nucleophile at an elevated temperature in the presenceof microwave radiation. Nucleophiles contemplated for use in thepractice of this particular disclosure include, but are not limited to,2-aminoethanol, 3-aminopropanol, 1,8-diazabicyclo[5.4.0]undec-7ene,1,4-diazabicyclo[2.2.2]octane, trialkylamine, sodium borohydride,lithium borohydride, lithium trialkylborohydride, lithium hydride,potassium hydride, and sodium hydride. Solvents contemplated for use inthe practice of this particular disclosure include, but are not limitedto, polar solvents such as 1,4-dioxane, acetone, acetonitrile,dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or suitable mixtures thereof. The process is carried out inthe presence of focused microwave radiation using a quartz reactor at apressure from about 1 Bar to about 25 Bar, a power setting from about 1W per liter of solvent to about 900 W per liter of solvent, at atemperature from about 0° C. to about 500° C., for about 0.01 to about 5hours, at a pH from about 1 to about 14.

In another embodiment is provided the use of a compound havingstructural formula III for the manufacture of a compound havingstructural formula I.

In one embodiment, disclosed herein is a process for preparing acompound having structural formula I wherein R₁-R₂₇ are independentlyselected from the group consisting of hydrogen and deuterium. Such aprocess can be performed, for example, by reacting a compound havingstructural formula III, wherein R₅₈-R₈₂ are independently selected fromthe group consisting of hydrogen and deuterium, under conditionssuitable to form a compound having structural formula I, as set forthbelow:

Compounds having structural formula III can be prepared by methods knownto one of skill in the art or following procedures similar to thosedescribed in the Example section herein and routine modificationsthereof. Compound III is contacted with formic acid or d₂-formic acidand an additive at an elevated temperature. Additives contemplated foruse in the practice of this particular disclosure include, but are notlimited to, lithium deuteroxide, lithium hydroxide, sodium deuteroxide,sodium hydroxide, potassium deuteroxide, potassium hydroxide, lithiumformate, potassium formate, and sodium formate. Solvents contemplatedfor use in the practice of this particular disclosure include, but arenot limited to, polar solvents such as water, deuterium oxide, methanol,d₄-methanol, formic acid, d₂-formic acid, 1,4-dioxane, acetone,acetonitrile, dimethylformamide, dim ethyl acetamide, N-methylpyrrolidone, dimethylsulfoxide, or any suitable mixtures thereof. Theprocess is carried out at a temperature from about 0° C. to about 500°C., for about 0.01 to about 240 hours, at a pH from about 1 to about 14,at a pressure from about 1 mBar to about 350 Bar.

In certain embodiments, compounds having structural formula III arecontacted with a nucleophile at an elevated temperature in the presenceof microwave radiation. Additives contemplated for use in the practiceof this particular disclosure include, but are not limited to, lithiumdeuteroxide, lithium hydroxide, sodium deuteroxide, sodium hydroxide,potassium deuteroxide, potassium hydroxide, lithium formate, potassiumformate, and sodium formate. Solvents contemplated for use in thepractice of this particular disclosure include, but are not limited to,polar solvents such as water, deuterium oxide, methanol, d₄-methanol,formic acid, d₂-formic acid, 1,4-dioxane, acetone, acetonitrile,dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or any suitable mixtures thereof. The process is carried outin the presence of focused microwave radiation using a quartz reactor ata pressure from about 1 Bar to about 25 Bar, a power setting from about1 W per liter of solvent to about 900 W per liter of solvent, at atemperature from about 0° C. to about 500° C., for about 0.01 to about 5hours, at a pH from about 1 to about 14.

In certain embodiments, a compound as disclosed herein contains about60% or more by weight of the (−)-enantiomer of the compound and about40% or less by weight of (+)-enantiomer of the compound. In certainembodiments, a compound as disclosed herein contains about 70% or moreby weight of the (−)-enantiomer of the compound and about 30% or less byweight of (+)-enantiomer of the compound. In certain embodiments, acompound as disclosed herein contains about 80% or more by weight of the(−)-enantiomer of the compound and about 20% or less by weight of(+)-enantiomer of the compound. In certain embodiments, a compound asdisclosed herein contains about 90% or more by weight of the(−)-enantiomer of the compound and about 10% or less by weight of the(+)-enantiomer of the compound. In certain embodiments, a compound asdisclosed herein contains about 95% or more by weight of the(−)-enantiomer of the compound and about 5% or less by weight of(+)-enantiomer of the compound. In certain embodiments, a compound asdisclosed herein contains about 99% or more by weight of the(−)-enantiomer of the compound and about 1% or less by weight of(+)-enantiomer of the compound.

The deuterated compounds as disclosed herein may also contain lessprevalent isotopes for other elements, including, but not limited to,¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵N for nitrogen,and ¹⁷O or ¹⁸O for oxygen.

In certain embodiments, without being bound by any theory, a compounddisclosed herein may expose a patient to a maximum of about 0.000005%D₂O or about 0.00001% DHO, assuming that all of the C-D bonds in thecompound as disclosed herein are metabolized and released as D₂O or DHO.This quantity is a small fraction of the naturally occurring backgroundlevels of D₂O or DHO in circulation. In certain embodiments, the levelsof D₂O shown to cause toxicity in animals is much greater than even themaximum limit of exposure because of the deuterium enriched compound asdisclosed herein. Thus, in certain embodiments, the deuterium-enrichedcompound disclosed herein should not cause any additional toxicitybecause of the use of deuterium.

In one embodiment, the deuterated compounds disclosed herein maintainthe beneficial aspects of the corresponding non-isotopically enrichedmolecules while substantially increasing the maximum tolerated dose,decreasing toxicity, increasing the half-life (T_(1/2)), lowering themaximum plasma concentration (C_(max)) of the minimum efficacious dose(MED), lowering the efficacious dose and thus decreasing thenon-mechanism-related toxicity, and/or lowering the probability ofdrug-drug interactions.

Isotopic hydrogen can be introduced into a compound as disclosed hereinby synthetic techniques that employ deuterated reagents, wherebyincorporation rates are pre-determined; and/or by exchange techniques,wherein incorporation rates are determined by equilibrium conditions,and may be highly variable depending on the reaction conditions.Synthetic techniques, where tritium or deuterium is directly andspecifically inserted by tritiated or deuterated reagents of knownisotopic content, may yield high tritium or deuterium abundance, but canbe limited by the chemistry required. Exchange techniques, on the otherhand, may yield lower tritium or deuterium incorporation, often with theisotope being distributed over many sites on the molecule.

Compounds having the structural formulae below can be prepared bymethods known to one of skill in the art or following procedures similarto those described in the Example section herein and routinemodifications thereof. In the Schemes below, deuterated intermediatesare either commercially available or can be prepared by methods known toone of skill in the art or following procedures similar to thosedescribed in the Example section herein and routine modificationsthereof.

For example, a compound having structural formula I can be prepared asshown in Scheme 1.

Phenol 4 reacts with methyl iodide and a deprotonating agent, such aspotassium carbonate, to give ether 5, which reacts with cyclohexanone 6in the presence of a deprotonating agent, such as sodium hydroxide, anda phase transfer catalyst, such tetra-n-butyl ammonium hydrogen sulfate,to give nitrile 7. Compound 7 is reduced to aminoalcohol 8 under ahydrogen atmosphere in the presence of a catalyst, such as rhodium onalumina. Alternatively, alcohol 7 is dissolved in ammonia in methanoland reduced to aminoalcohol 8 using a continuous flow hydrogenationreactor equipped with a Raney Ni catalyst cartridge. Compound 8 reactswith excess methyl iodide to give the corresponding quaternary salt II(similar to the reaction step shown in scheme 2) which is demethylatedwith a nucleophile, such as 2-aminoethanol or 3-aminopropanol, at anelevated temperature to produce the compound of formula I as the freebase. The hydrochloride salt of the compound of Formula I can beprepared by methods known in the art.

Deuterium can be incorporated to different positions synthetically,according to the synthetic procedures as shown in Scheme 1, by usingappropriate deuterated intermediates. For example, to introducedeuterium at one or more positions selected from R₁, R₂, R₃, R₁₁, R₁₂,R₁₃, R₁₄, R₁₅, and R₁₆, methyl iodide with the corresponding deuteriumsubstitutions can be used.

By way of another example, a compound having structural formula II canbe prepared as shown in Scheme 2.

Compound 9 is prepared as in Scheme 1 and reacts with excess methyliodide to produce the compound of formula II as the iodide salt.

Deuterium can be incorporated to different positions synthetically,according to the synthetic procedures as shown in Scheme 1, by usingappropriate deuterated intermediates. For example, to introducedeuterium at one or more positions selected from R₂₈, R₂₉, R₃₀, R₄₉,R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, and R₅₇ methyl iodide with thecorresponding deuterium substitutions can be used.

By way of another example, a compound having structural formula III orstructural formula I can be prepared as shown in Scheme 3.

Compound 10 is prepared as in Scheme 1 and reacts with formic acid andformaldehyde at an elevated temperature to produce the compound offormula III. The compound of formula III reacts with formic acid and adeprotonating agent, such as sodium hydroxide or sodium formate, toproduce the compound of formula I. The hydrochloride salt of thecompound of formula I can be prepared by methods known in the art.

Deuterium can be incorporated to different positions synthetically,according to the synthetic procedures as shown in Scheme 3, by usingappropriate deuterated intermediates. For example, to introducedeuterium at one or more positions selected from R₆₈, R₆₉, R₈₀, R₈₁, andR₈₂, formic acid and formaldehyde with the corresponding deuteriumsubstitutions can be used. To introduce deuterium at one or morepositions selected from R₅₈, R₅₉, and R₆₀, methyl iodide with thecorresponding deuterium substitutions can be used.

By way of example, a compound having structural formula IV or structuralformula can be prepared as shown in Scheme 4.

Compound 11 is prepared as in Scheme 1-3 and reacts with a demethylatingagent to produce the compound of formula IV.

Deuterium can be incorporated to different positions synthetically,according to the synthetic procedures as shown in Scheme 4, by usingappropriate deuterated intermediates as described in Schemes 1-3.

It is to be understood that the compounds disclosed herein may containone or more chiral centers, chiral axes, and/or chiral planes, asdescribed in “Stereochemistry of Carbon Compounds” Eliel and Wilen, JohnWiley & Sons, New York, 1994, pp. 1119-1190. Such chiral centers, chiralaxes, and chiral planes may be of either the (R) or (S) configuration,or may be a mixture thereof.

Another method for characterizing a composition containing a compoundhaving at least one chiral center is by the effect of the composition ona beam of polarized light. When a beam of plane polarized light ispassed through a solution of a chiral compound, the plane ofpolarization of the light that emerges is rotated relative to theoriginal plane. This phenomenon is known as optical activity, andcompounds that rotate the plane of polarized light are said to beoptically active. One enantiomer of a compound will rotate the beam ofpolarized light in one direction, and the other enantiomer will rotatethe beam of light in the opposite direction. The enantiomer that rotatesthe polarized light in the clockwise direction is the (+) enantiomer andthe enantiomer that rotates the polarized light in the counterclockwisedirection is the (−) enantiomer. Included within the scope of thecompositions described herein are compositions containing between 0 and100% of the (+) and/or (−) enantiomer of compounds disclosed herein.

Where a compound as disclosed herein contains an alkenyl or alkenylenegroup, the compound may exist as one or mixture of geometric cis/trans(or Z/E) isomers. Where structural isomers are interconvertible via alow energy barrier, the compound as disclosed herein may exist as asingle tautomer or a mixture of tautomers. This can take the form ofproton tautomerism in the compound as disclosed herein that contains forexample, an imino, keto, or oxime group; or so-called valencetautomerism in the compound that contain an aromatic moiety. It followsthat a single compound may exhibit more than one type of isomerism.

The compounds disclosed herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, a racemic mixture, or adiastereomeric mixture. As such, one of skill in the art will recognizethat administration of a compound in its (R) form is equivalent, forcompounds that undergo epimerization in vivo, to administration of thecompound in its (S) form. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemateusing, for example, chiral chromatography, recrystallization,resolution, diastereomeric salt formation, or derivatization intodiastereomeric adducts followed by separation.

When the compound as disclosed herein contains an acidic or basicmoiety, it may also disclosed as a pharmaceutically acceptable salt(See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook ofPharmaceutical Salts, Properties, and Use,” Stah and Wermuth, Ed.;Wiley-VCH and VHCA, Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptableacid addition salts include, but are not limited to, acetic acid,2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginicacid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoicacid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaricacid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionicacid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablebasic addition salts, including, but not limited to, inorganic bases,such as magnesium hydroxide, calcium hydroxide, potassium hydroxide,zinc hydroxide, or sodium hydroxide; and organic bases, such as primary,secondary, tertiary, and quaternary, aliphatic and aromatic amines,including L-arginine, benethamine, benzathine, choline, deanol,diethanolamine, diethylamine, dimethylamine, dipropylamine,diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine,ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,methylamine, piperidine, piperazine, propylamine, pyrrolidine,1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,isoquinoline, secondary amines, triethanolamine, trimethylamine,triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound as disclosed herein may also be designed as a prodrug,which is a functional derivative of the compound as disclosed herein andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

Pharmaceutical Compositions

Disclosed herein are pharmaceutical compositions comprising a compoundas disclosed herein as an active ingredient, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, in combination with one ormore pharmaceutically acceptable excipients or carriers.

Disclosed herein are pharmaceutical compositions in modified releasedosage forms, which comprise a compound as disclosed herein and one ormore release controlling excipients or carriers as described herein.Suitable modified release dosage vehicles include, but are not limitedto, hydrophilic or hydrophobic matrix devices, water-soluble separatinglayer coatings, enteric coatings, osmotic devices, multiparticulatedevices, and combinations thereof. The pharmaceutical compositions mayalso comprise non-release controlling excipients or carriers.

Further disclosed herein are pharmaceutical compositions in entericcoated dosage forms, which comprise a compound as disclosed herein andone or more release controlling excipients or carriers for use in anenteric coated dosage form. The pharmaceutical compositions may alsocomprise non-release controlling excipients or carriers.

Further disclosed herein are pharmaceutical compositions in effervescentdosage forms, which comprise a compound as disclosed herein and one ormore release controlling excipients or carriers for use in aneffervescent dosage form. The pharmaceutical compositions may alsocomprise non-release controlling excipients or carriers.

Additionally disclosed are pharmaceutical compositions in a dosage formthat has an instant releasing component and at least one delayedreleasing component, and is capable of giving a discontinuous release ofthe compound in the form of at least two consecutive pulses separated intime from 0.1 up to 24 hours. The pharmaceutical compositions comprise acompound as disclosed herein and one or more release controlling andnon-release controlling excipients or carriers, such as those excipientsor carriers suitable for a disruptable semipermeable membrane and asswellable substances.

Disclosed herein also are pharmaceutical compositions in a dosage formfor oral administration to a subject, which comprise a compound asdisclosed herein and one or more pharmaceutically acceptable excipientsor carriers, enclosed in an intermediate reactive layer comprising agastric juice-resistant polymeric layered material partially neutralizedwith alkali and having cation exchange capacity and a gastricjuice-resistant outer layer.

Pharmaceutical compositions are provided herein which comprise about 0.1to about 1000 mg, about 1 to about 500 mg, about 2 to about 100 mg,about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 20mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 500 mg ofone or more compounds as disclosed herein.

In certain embodiments, the pharmaceutical compositions are in the formof immediate-release capsules for oral administration, and may furthercomprise cellulose, iron oxides, lactose, magnesium stearate, and sodiumstarch glycolate.

In certain embodiments, the pharmaceutical compositions are in the formof delayed-release capsules for oral administration, and may furthercomprise cellulose, ethylcellulose, gelatin, hypromellose, iron oxide,and titanium dioxide.

In certain embodiments, the pharmaceutical compositions are in the formof enteric coated delayed-release tablets for oral administration, andmay further comprise carnauba wax, crospovidone, diacetylatedmonoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellosephthalate, magnesium stearate, mannitol, sodium hydroxide, sodiumstearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

In certain embodiments, the pharmaceutical compositions are in the formof enteric coated delayed-release tablets for oral administration, andmay further comprise calcium stearate, crospovidone, hydroxypropylmethylcellulose, iron oxide, mannitol, methacrylic acid copolymer,polysorbate 80, povidone, propylene glycol, sodium carbonate, sodiumlauryl sulfate, titanium dioxide, and triethyl citrate.

The compound as disclosed herein may be administered alone or incombination with one or more other active ingredients. Pharmaceuticalcompositions comprising a compound disclosed herein may be formulated invarious dosage forms for oral, parenteral, and topical administration.The pharmaceutical compositions may also be formulated as a modifiedrelease dosage form, including delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-,programmed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Delivery Technology,Rathbone et al., Eds., Drugs and the Pharmaceutical Science, MarcelDekker, Inc.: New York, N.Y., 2002; Vol. 126).

The pharmaceutical compositions disclosed herein may be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the compounds may be administered chronically, thatis, for an extended period of time, including throughout the duration ofthe patient's life in order to ameliorate or otherwise control or limitthe symptoms of the patient's disease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the compounds may be given continuously or temporarilysuspended for a certain length of time (i.e., a “drug holiday”).

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disorder is retained.Patients can, however, require intermittent treatment on a long-termbasis upon any recurrence of symptoms.

Any of the pharmaceutical formulations described herein can comprise (asthe active component) at least one of the hydrochloride salt Forms A-Fof formula I, or further contain (as the active component) substantiallyonly one or more of the hydrochloride salt Forms A-F of formula I.

A. Oral Administration

The pharmaceutical compositions disclosed herein may be provided insolid, semisolid, or liquid dosage forms for oral administration. Asused herein, oral administration also include buccal, lingual, andsublingual administration. Suitable oral dosage forms include, but arenot limited to, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, bulk powders,effervescent or non-effervescent powders or granules, solutions,emulsions, suspensions, solutions, wafers, sprinkles, elixirs, andsyrups. In addition to the active ingredient(s), the pharmaceuticalcompositions may contain one or more pharmaceutically acceptablecarriers or excipients, including, but not limited to, binders, fillers,diluents, disintegrants, wetting agents, lubricants, glidants, coloringagents, dye-migration inhibitors, sweetening agents, and flavoringagents.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The binder or filler may be present fromabout 50 to about 99% by weight in the pharmaceutical compositionsdisclosed herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of disintegrant in thepharmaceutical compositions disclosed herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions disclosed herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsdisclosed herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (CabotCo. of Boston, Mass.), and asbestos-free talc. Coloring agents includeany of the approved, certified, water soluble FD&C dyes, and waterinsoluble FD&C dyes suspended on alumina hydrate, and color lakes andmixtures thereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Flavoring agents include natural flavorsextracted from plants, such as fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation, such as peppermint and methylsalicylate. Sweetening agents include sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include gelatin, acacia,tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitanmonooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN®80), and triethanolamine oleate. Suspending and dispersing agentsinclude sodium carboxymethylcellulose, pectin, tragacanth, Veegum,acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrolidone. Preservatives include glycerin, methyl andpropylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether. Solvents includeglycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueousliquids utilized in emulsions include mineral oil and cottonseed oil.Organic acids include citric and tartaric acid. Sources of carbondioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions disclosed herein may be disclosed ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenylsalicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions disclosed herein may be disclosed assoft or hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms disclosed herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The pharmaceutical compositions disclosed herein may be disclosed inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquids or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term“lower” means an alkyl having between 1 and 6 carbon atoms), e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) disclosed herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions disclosed herein for oral administrationmay be also disclosed in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions disclosed herein may be disclosed asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions disclosed herein may be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction, such as drotrecogin-α, and hydrocortisone.

B. Parenteral Administration

The pharmaceutical compositions disclosed herein may be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions disclosed herein may be formulated inany dosage forms that are suitable for parenteral administration,including solutions, suspensions, emulsions, micelles, liposomes,microspheres, nanosystems, and solid forms suitable for solutions orsuspensions in liquid prior to injection. Such dosage forms can beprepared according to conventional methods known to those skilled in theart of pharmaceutical science (see, Remington: The Science and Practiceof Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzates, thimerosal, benzalkonium chloride,benzethonium chloride, methyl- and propyl-parabens, and sorbic acid.Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfate and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions disclosed herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are disclosed asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are disclosed as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are disclosed as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare disclosed as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are disclosed as ready-to-use sterile emulsions.

The pharmaceutical compositions may be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsdisclosed herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions disclosed herein may be administeredtopically to the skin, orifices, or mucosa. Topical administration, asdescribed herein, includes (intra)dermal, conjuctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,uretheral, respiratory, and rectal administration.

The pharmaceutical compositions disclosed herein may be formulated inany dosage forms that are suitable for topical administration for localor systemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, dermal patches. Thetopical formulation of the pharmaceutical compositions disclosed hereinmay also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations disclosed herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions may also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions disclosed herein may be disclosed in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including such as lard, benzoinatedlard, olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Cream vehiclesmay be water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase is also called the “internal” phase, whichis generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation may be a nonionic, anionic, cationic,or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include crosslinked acrylicacid polymers, such as carbomers, carboxypolyalkylenes, Carbopol®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methylcellulose; gums, such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

The pharmaceutical compositions disclosed herein may be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions disclosed herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, polyacrylic acid; glycerinated gelatin. Combinations ofthe various vehicles may be used. Rectal and vaginal suppositories maybe prepared by the compressed method or molding. The typical weight of arectal and vaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions disclosed herein may be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions disclosed herein may be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions may be disclosed in the form of an aerosolor solution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions mayalso be disclosed as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer may be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient disclosedherein, a propellant as solvent; and/or an surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions disclosed herein may be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes may beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters and cartridges for use in an inhaler or insufflatormay be formulated to contain a powder mix of the pharmaceuticalcompositions disclosed herein; a suitable powder base, such as lactoseor starch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include dextran,glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.The pharmaceutical compositions disclosed

-   -   herein for inhaled/intranasal administration may further        comprise a suitable flavor, such as menthol and levomenthol, or        sweeteners, such as saccharin or saccharin sodium.

The pharmaceutical compositions disclosed herein for topicaladministration may be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions disclosed herein may be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. The pharmaceuticalcompositions in modified release dosage forms can be prepared using avariety of modified release devices and methods known to those skilledin the art, including, but not limited to, matrix controlled releasedevices, osmotic controlled release devices, multiparticulate controlledrelease devices, ion-exchange resins, enteric coatings, multilayeredcoatings, microspheres, liposomes, and combinations thereof. The releaserate of the active ingredient(s) can also be modified by varying theparticle sizes and polymorphorism of the active ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions disclosed herein in a modified releasedosage form may be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al in “Encyclopedia ofControlled Drug Delivery,” Vol. 2, Mathiowitz ed., Wiley, 1999).

In one embodiment, the pharmaceutical compositions disclosed herein in amodified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including synthetic polymers, and naturally occurring polymers andderivatives, such as polysaccharides and proteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; and cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acidesters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acidor methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylicacid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In further embodiments, the pharmaceutical compositions are formulatedwith a non-erodible matrix device. The active ingredient(s) is dissolvedor dispersed in an inert matrix and is released primarily by diffusionthrough the inert matrix once administered. Materials suitable for useas a non-erodible matrix device included, but are not limited to,insoluble plastics, such as polyethylene, polypropylene, polyisoprene,polyisobutylene, polybutadiene, polymethylmethacrylate,polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride,methyl acrylate-methyl methacrylate copolymers, ethylene-vinylacetatecopolymers, ethylene/propylene copolymers, ethylene/ethyl acrylatecopolymers, vinylchloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate,butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethyleneterephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers, and;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate,and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions disclosed herein in a modified releasedosage form may be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions disclosed herein in a modified releasedosage form may be fabricated using an osmotic controlled releasedevice, including one-chamber system, two-chamber system, asymmetricmembrane technology (AMT), and extruding core system (ECS). In general,such devices have at least two components: (a) the core which containsthe active ingredient(s); and (b) a semipermeable membrane with at leastone delivery port, which encapsulates the core. The semipermeablemembrane controls the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion through thedelivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels,”including, but not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents are osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol, organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates may be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MannogemeEZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core may also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane may also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane may be formedpost-coating by mechanical or laser drilling. Delivery port(s) may alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports may be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform may further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions disclosed hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions disclosed hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions disclosed herein in a modified releasedosage form may be fabricated a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates may be made by the processes know to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein may be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles may themselves constitute themultiparticulate device or may be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions disclosed herein may also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359;6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082;6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252;5,840,674; 5,759,542; and 5,709,874.

Polymorphs of Compounds of Formula I

The hydrochloride salt Forms A-F of the compound of formula I have beencharacterized using X-ray powder diffractometry. The hydrochloride saltForms A-F of the compound of Formula I provide X-ray powder diffractionpatterns substantially the same as shown in FIGS. 1-6.

The hydrochloride salt Form A ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol(d₉-venlafaxine) of the present disclosure is characterized in that thecrystal provides high-intensity diffraction peaks at diffraction anglesof 2-theta (2θ) in a X-ray powder diffraction spectrum of about 6.703,8.321, 12.681, 13.5, 15.54, 18.918, 20.359, 21.161, 21.762, 25.04, and28.518.

The hydrochloride salt Form B ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol(d₉-venlafaxine) of the present disclosure is characterized in that thecrystal provides high-intensity diffraction peaks at diffraction anglesof 2-theta (2θ) in a X-ray powder diffraction spectrum of about 6.683,10.201, 13.441, 15.517, 18.198, 19.719, 20.258, 21.68, 22.658, 25.543,28.022, and 35.02.

The hydrochloride salt Form C ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol(d₉-venlafaxine) of the present disclosure is characterized in that thecrystal provides high-intensity diffraction peaks at diffraction anglesof 2-theta (2θ) in a X-ray powder diffraction spectrum of about 6.718,8.335, 12.68, 13.5, 15.539, 16.282, 18.902, 19.737, 20.34, 21.161,21.758, 25.02, 25.601, 26.261, 28.518, 31.54, 33.198, 33.937, and35.159.

The hydrochloride salt Form D ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol(d₉-venlafaxine) of the present disclosure is characterized in that thecrystal provides high-intensity diffraction peaks at diffraction anglesof 2-theta (2θ) in a X-ray powder diffraction spectrum of about 6.74,7.421, 8.341, 10.219, 12.7, 13.502, 17.9, 15.541, 20.36, 21.221, 21.761,25.078, 31.04, 34.018, and 35.139.

The hydrochloride salt Form E ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol(d₉-venlafaxine) of the present disclosure is characterized in that thecrystal provides high-intensity diffraction peaks at diffraction anglesof 2-theta (2θ) in a X-ray powder diffraction spectrum of about 5.597,7.182, 9.078, 9.557, 11.201, 14.46, 14.76, 16.86, 17.497, 19.201,19.619, 20.241, 20.66, 21.76, 22.596, 23.06, 24.4, 25.02, 26.519,26.842, 31.52, and 35.438.

The hydrochloride salt Form F ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol(d₉-venlafaxine) of the present disclosure is characterized in that thecrystal provides high-intensity diffraction peaks at diffraction anglesof 2-theta (2θ) in a X-ray powder diffraction spectrum of about 5.581,7.186, 11.22, 14.499, 14.802, 16.882, 19.242, 20.317, 21.798, 22.637,and 35.445.

In the infrared absorption spectra FIGS. 7-12 the horizontal axis showsthe wavenumber in cm⁻¹ and the vertical axis shows the transmittance inpercent (%).

The hydrochloride salt ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₉-venlafaxine) has been characterized by X-ray powder diffractometry.

The hydrochloride crystals ofd₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₉-venlafaxine, Forms A-F) provide powder X-ray diffraction spectrumssubstantially the same as the powder X-ray diffraction spectrums shownin FIGS. 1-6, respectively. However, it is known that a powder X-raydiffraction spectrum may be obtained with a measurement error dependingon measurement conditions. In particular, it is generally known thatintensities in a powder X-ray diffraction spectrum may fluctuatedepending on measurement conditions. Therefore, it should be understoodthat the salts of the present disclosure are not limited to the crystalsthat provide X-ray powder diffraction spectrum completely identical tothe X-ray powder diffraction spectrums shown in FIGS. 1-6, and that anycrystals providing X-ray powder diffraction spectrums substantially thesame as the aforementioned X-ray powder diffraction spectrums fallwithin the scope of the present disclosure. Those skilled in the fieldof X-ray powder diffractometry can readily judge the substantialidentity of X-ray powder diffraction spectrums.

Generally, a measurement error of diffraction angle for a usual X-raypowder diffractometry is about 5% or less, and such degree of ameasurement error should be taken into account as to diffraction angles.Furthermore, it should be understood that intensities may fluctuatedepending on experimental conditions.

The hydrochloride salt Form A of the compound of formula I ischaracterized in that the crystal provides high-intensity diffractionpeaks at diffraction angles of about 2-theta, [% relative intensity]:6.703 [29.3], 8.321 [19], 12.681 [77.5], 13.5 [47.9], 15.54 [17.7],18.918 [24.4], 20.359 [100], 21.161 [38.3], 21.762 [26.1], 25.04 [27.8],and 28.518 [18.2]. The hydrochloride salt Form A of the presentdisclosure provides a X-ray powder diffraction spectrum substantiallythe same as the X-ray diffraction spectrum shown in FIG. 1.

The characteristic 2-theta (2θ) values and relative intensity (RI) inpercentage for the diffraction spectrum of the hydrochloride salt Form Aof the compound of Formula I is shown in Table 1. Thus, described hereinis a polymorph of the hydrochloride salt of Formula I having at leastfour of the most intense peaks presented in Table 1.

TABLE 1 2-theta RI 6.703 29.3 7.399 9 8.321 19 8.52 2.7 10.195 3.612.681 77.5 13.5 47.9 14.863 9.3 15.54 17.7 15.92 3.8 16.299 11.4 16.7628.1 17.318 4.6 18.5 4.2 18.918 24.4 19.757 6.1 20.359 100 21.161 38.321.762 26.1 22.196 2 22.92 2.8 24.084 1.7 25.04 27.8 25.34 5.3 25.641 826.261 6.4 26.481 4.9 26.866 1.6 27.265 6.7 28.518 18.2 28.822 6.230.419 2.5 31.001 7.9 31.539 10.5 32.456 2.1 32.758 3.3 33.162 7.333.957 10.4 35.181 15.5 36.024 1.8 36.399 1.6 36.814 2 37.76 3 38.68 5.139.159 2.2

The hydrochloride salt Form B of the compound of formula I ischaracterized in that the crystal provides high-intensity diffractionpeaks at diffraction angles of about 2-theta, [% relative intensity]:6.683 [15.5], 10.201 [93.6], 13.441 [27.8], 15.517 [66.2], 18.198 [41],19.719 [34.1], 20.258 [100], 21.68 [71.2], 22.658 [24.8], 25.543[22.4],28.022 [20.9], and 35.02 [33.4]. The hydrochloride salt Form B ofthe present disclosure provides a x-ray powder diffraction spectrumsubstantially the same as the X-ray diffraction spectrum shown in FIG.2.

The characteristic 2-theta (2θ) values and relative intensity (RI) inpercentage for the diffraction spectrum of the hydrochloride salt Form Bof the compound of formula I is shown in Table 2. Thus, described hereinis a polymorph of the hydrochloride salt of formula I having at leastfour of the most intense peaks presented in Table 2.

TABLE 2 2-theta RI 2-theta RI 2-theta RI 6.683 15.5 22.658 24.8 31.3798.2 10.201 93.6 23.923 2.7 31.978 9.1 13.441 27.8 25.322 9.6 32.28 10.515.014 7.6 25.543 22.4 32.701 6.5 15.517 66.2 26.502 6.7 32.981 2.316.458 1.5 27.122 9.5 34.12 9.1 16.84 10.3 27.557 5.5 35.02 33.4 17.2062.7 28.022 20.9 36.024 3.1 18.198 41 28.64 4.4 36.842 2.6 19.719 34.129.241 10.6 37.5 6.7 20.258 100 29.659 7.1 38.341 3.9 21.68 71.2 31.07911.9 38.753 1.2

The hydrochloride salt Form C of the compound of formula I ischaracterized in that the crystal provides high-intensity diffractionpeaks at diffraction angles of about 2-theta, [% relative intensity]:6.718 [21.4], 8.335 [20.6], 12.68 [80], 13.5 [40.7], 15.539 [20.2],16.282 [24.3], 18.902 [48.9], 19.737 [17.4], 20.34 [100], 21.161 [79.4],21.758 [30.5], 25.02 [31.5], 25.601 [18.9], 26.261 [15.2], 28.518[30.2], 31.54 [18.7], 33.198 [14.2], 33.937 [16.5], and 35.159 [21.3].The hydrochloride salt Form C of the present disclosure provides a X-raypowder diffraction spectrum substantially the same as the X-raydiffraction spectrum shown in FIG. 3.

The characteristic 2-theta (2θ) values and relative intensity (RI) inpercentage for the diffraction spectrum of the hydrochloride salt Form Cof the compound of formula I is shown in Table 3. Thus, described hereinis a polymorph of the hydrochloride salt of formula I having at leastfour of the most intense peaks presented in Table 3.

TABLE 3 2-theta RI 6.718 21.4 8.335 20.6 10.18 9.1 12.68 80 13.5 40.715.539 20.2 15.68 11.5 15.938 9.4 16.282 24.3 16.778 9.9 16.916 9.517.302 8.2 18.182 4.2 18.4 3 18.902 48.9 19.737 17.4 20.34 100 21.16179.4 21.758 30.5 22.151 3.6 22.659 2.1 22.955 2.4 24.073 1.7 25.02 31.525.36 11.1 25.601 18.9 26.261 15.2 26.856 3.2 27.258 8.8 28.518 30.228.839 11.6 30.42 2.4 30.962 11.7 31.54 18.7 32.478 4.6 32.775 3.933.198 14.2 33.937 16.5 35.159 21.3 36.076 3.1 36.438 2.7 36.765 3.937.66 5.6 38.207 2.2 38.658 6.7 39.2 3.6

The hydrochloride salt Form D of the compound of formula I ischaracterized in that the crystal provides high-intensity diffractionpeaks at diffraction angles of about 2-theta, [% relative intensity]:6.74 [21.2], 7.421 [14], 8.341 [35.5], 10.219 [23], 12.7 [99.5], 13.502[40.7], 17.9 [17.5], 15.541 [37.3], 20.36 [100], 21.221 [23.7], 21.761[41], 25.078 [26.3], 31.04 [17.7], 34.018 [14.8], and 35.139 [22.7]. Thehydrochloride salt Form D of the present disclosure provides a X-raypowder diffraction spectrum substantially the same as the X-raydiffraction spectrum shown in FIG. 4.

The characteristic 2-theta (2θ) values and relative intensity (RI) inpercentage for the diffraction spectrum of the hydrochloride salt Form Dof the compound of formula I is shown in Table 4. Thus, described hereinis a polymorph of the hydrochloride salt of formula I having at leastfour of the most intense peaks presented in Table 4.

TABLE 4 2-theta RI 6.74 21.2 7.421 14 8.341 35.5 10.219 23 12.7 99.513.502 40.7 17.9 17.5 15.541 37.3 16.361 9.9 16.764 13 17.424 3 18.27610.2 18.54 7.2 18.96 12.1 19.741 12 20.36 100 21.221 23.7 21.761 4122.279 2.2 22.719 4.9 23.039 3 24.024 3.2 25.078 26.3 25.383 5.9 25.6049.7 26.303 6 26.483 8.9 26.959 6.9 27.258 7.1 28.223 7.3 28.518 11.928.919 4.8 29.322 3.2 30.419 3.2 31.04 17.7 31.66 10.6 32.742 4 33.2395.4 34.018 14.8 35.139 22.7 36.1 2.5 36.388 1.8 36.839 2.2 37.719 3.538.681 5.5 39.198 3.8

The hydrochloride salt Form E of the compound of formula I ischaracterized in that the crystal provides high-intensity diffractionpeaks at diffraction angles of about 2-theta, [% relative intensity]:5.597 [28], 7.182 [36.2], 9.078 [24.1], 9.557 [14.9], 11.201 [100],14.46 [40.2], 14.76 [40.4], 16.86 [71.7], 17.497 [15.7], 19.201 [66.5],19.619 [19.6], 20.241 [35.2], 20.66 [19.6], 21.76 [22.5], 22.596 [26.4],23.06 [13.2], 24.4 [15.3], 25.02 [12.1], 26.519 [13.5], 26.842 [18.7],31.52 [12.6], and 35.438 [17.9]. The hydrochloride salt Form E of thepresent disclosure provides an X-ray powder diffraction spectrumsubstantially the same as the X-ray diffraction spectrum shown in FIG.5.

The characteristic 2-theta (2θ) values and relative intensity (RI) inpercentage for the diffraction spectrum of the hydrochloride salt Form Eof the compound of formula I is shown in Table 5. Thus, described hereinis a polymorph of the hydrochloride salt of formula I having at leastfour of the most intense peaks presented in Table 5.

TABLE 5 2-theta RI 5.597 28 7.182 36.2 9.078 24.1 9.557 14.9 10.663 911.201 100 12.104 2.4 12.361 1.2 13.422 2.1 13.921 4.4 14.46 40.2 14.7640.4 15.366 3.2 15.721 11.2 16.041 8.4 16.86 71.7 17.497 15.7 17.866 318.398 12.8 19.201 66.5 19.619 19.6 20.241 35.2 20.66 19.6 20.879 11.221.76 22.5 22.596 26.4 23.06 13.2 23.994 2 24.4 15.3 25.02 12.1 25.6433.9 25.861 6.7 26.519 13.5 26.842 18.7 27.502 5.1 28.422 6.1 28.859 7.229.937 3.1 30.98 7.7 31.52 12.6 32.362 6.4 32.721 6 33.162 2.1 34.4619.6 35.438 17.9 35.899 5.6 36.779 4.7 37.4 4.5 37.984 2 38.962 3.6

The hydrochloride salt Form F of the compound of formula I ischaracterized in that the crystal provides high-intensity diffractionpeaks at diffraction angles of about 2-theta, [% relative intensity]:5.581 [26.1], 7.186 [18.3],11.22 [100], 14.499 [18.8], 14.802 [20.5],16.882 [63.9], 19.242 [38.4], 20.317 [51.6], 21.798 [17.5], 22.637[26.3], and 35.445 [16.2]. The hydrochloride salt Form F of the presentdisclosure provides a X-ray powder diffraction spectrum substantiallythe same as the X-ray diffraction spectrum shown in FIG. 6.

The characteristic 2-theta (2θ) values and relative intensity (RI) inpercentage for the diffraction spectrum of the hydrochloride salt Form Fof the compound of formula I is shown in Table 6. Thus, described hereinis a polymorph of the hydrochloride salt of formula I having at least 4of the most intense peaks presented in Table 6.

TABLE 6 2-theta RI 5.581 26.1 6.688 6.4 7.186 18.3 9.079 7.7 9.576 9.110.206 2.4 10.735 4.4 11.22 100 12.133 3 13.447 9 13.963 2.2 14.499 18.814.802 20.5 15.559 5.1 15.796 6.1 16.087 3.6 16.882 63.9 17.519 10.618.407 5.6 19.242 38.4 19.68 11.8 20.317 51.6 20.72 8.8 20.923 6.321.798 17.5 22.637 26.3 23.101 9 24.425 11.9 25.042 7.1 25.921 7.726.587 5.4 26.939 10.1 27.194 5.3 27.579 2.5 28.435 3.9 28.921 3.5 29.41.6 29.808 2.6 31.064 3.7 31.597 9.1 32.374 1.6 33.32 1.3 34.524 6.335.112 4.7 35.445 16.2 35.88 1.3 36.727 2.3 36.981 3.2 37.464 2.9 39.0231.9 38.962 3.6

X-ray powder diffraction pattern is only one of many ways tocharacterize the arrangement of atoms comprising the hydrochloride saltof d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₉-venlafaxine, Forms A-F). Other methods are well known in the art,such as, single X-ray crystal diffraction, may be used to identifyaforementioned salt forms of compounds of formula I.

The hydrochloride salt Forms A-F of the compound of formula I have highcrystallinity, i.e., substantially free of amorphous material. Suchsalts provide more reproducible dosing results. The hydrochloride saltForms A-F of the compound of formula I are substantially hygroscopicallystable, which alleviates potential problems associated with weightchanges of the active ingredient during the manufacture of capsules ortablets. The hydrochloride Forms A-F of the compound of formula I alsohave a low tendency for concentrated aqueous solution to form viscousmixtures upon standing. The hydrochloride salt Forms A-F of the compoundof formula I have rapid kinetic aqueous solubility which simplifiesaqueous dosing and make them suitable for injectable dosage forms.Furthermore, the hydrochloride salt Forms A-F of the compound of formulaI with enhanced solubility characteristics facilitate the dissolution ofsolid dosage forms in a timely manner.

The hydrochloride salt Forms A-F of the compound of formula I havegreater kinetic solubility than the free base of the compound of formulaI. Additionally, the hydrochloride salt Forms A-F of the compound offormula I are more stable in air and can be used without deliquescence.

Methods of Use

Disclosed are methods for treating a monoamine-related disorder,comprising administering to a subject having or being suspected to havesuch a disorder, a therapeutically effective amount compound asdisclosed herein or a pharmaceutically acceptable salt, solvate, orprodrug thereof.

Monoamine-mediated disorders include, but are not limited to,psychotropic disorders, anxiety disorder, generalized anxiety disorder,depression, post-traumatic stress disorder, obsessive-compulsivedisorder, panic disorder, hot flashes, senile dementia, migraine,hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathicpain, painful diabetic retinopathy, bipolar depression, obstructivesleep apnea, psychiatric disorders, premenstrual dysphoric disorder,social phobia, social anxiety disorder, urinary incontinence, anorexia,bulimia nervosa, obesity, ischemia, head injury, calcium overload inbrain cells, drug dependence, Gilles de la Tourette syndrome, Shy Dragersyndrome, vasomotor flushing, chronic fatigue syndrome, cognitionenhancement, attention deficit hyperactivity disorder, fibromyalgia,irritable bowel syndrome, and/or premature ejaculation.

Also disclosed are methods of treating, preventing, or ameliorating oneor more symptoms of a disorder associated with serotonin and/ornorepinephrine receptors and/or transporters, by administering to asubject having or being suspected to have such a disorder atherapeutically effective amount of a compound as disclosed herein or apharmaceutically acceptable salt, solvate, or prodrug thereof.

Furthermore, disclosed herein are methods of modulating the activity ofserotonin and/or norepinephrine receptors and/or transporters,comprising contacting the receptors with at least one compound asdisclosed herein or a pharmaceutically acceptable salt, solvate, orprodrug thereof. In one embodiment, the serotonin and/or norepinephrinereceptor and/or transporter is expressed by a cell.

In certain embodiments, the inter-individual variation in plasma levelsof the compounds as disclosed herein, or metabolites thereof, isdecreased as defined herein.

Disclosed herein are methods for treating a subject, including a human,having or suspected of having a disorder comprising administering to thesubject a therapeutically effective amount of a compound as disclosedherein or a pharmaceutically acceptable salt, solvate, or prodrugthereof; so as to affect increased average plasma levels of the compoundor decreased average plasma levels of at least one metabolite of thecompound per dosage unit as compared to the correspondingnon-isotopically enriched compound.

In certain embodiments, the average plasma levels of the compounds asdisclosed herein are increased as defined herein.

In certain embodiments, the average plasma levels of a metabolite of thecompounds as disclosed herein are decreased as defined herein.

Plasma levels of the compounds as disclosed herein, or metabolitesthereof, are measured using the methods described by Li et al. (RapidCommunications in Mass Spectrometry 2005,19, 1943-1950).

Disclosed herein are methods for treating a subject, including a human,having or suspected of having a disorder comprising administering to thesubject a therapeutically effective amount of a compound as disclosedherein or a pharmaceutically acceptable salt, solvate, or prodrugthereof; so as to affect a decreased inhibition of, and/or metabolism byat least one cytochrome P₄₅₀ or monoamine oxidase isoform in the subjectduring the treatment of the disease as compared to the correspondingnon-isotopically enriched compound.

Examples of cytochrome P₄₅₀ isoforms in a mammalian subject include, butare not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6,CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2,CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11,CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1,CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2,CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39,CYP46, and CYP51.

Examples of monoamine oxidase isoforms in a mammalian subject include,but are not limited to, MAO_(A), and MAO_(B).

In certain embodiments, the decrease in inhibition of the cytochromeP₄₅₀ or monoamine oxidase isoform by a compound as disclosed herein isgreater than about 5%, greater than about 10%, greater than about 20%,greater than about 30%, greater than about 40%, or greater than about50% as compared to the corresponding non-isotopically enrichedcompounds.

The inhibition of the cytochrome P₄₅₀ isoform is measured by the methodof Ko et al. (British Journal of Clinical Pharmacology, 2000, 49,343-351). The inhibition of the MAO_(A) isoform is measured by themethod of Weyler et al. (J. Biol Chem. 1985, 260, 13199-13207). Theinhibition of the MAO_(B) isoform is measured by the method of Uebelhacket al. (Pharmacopsychiatry, 1998, 31, 187-192).

Disclosed herein are methods for treating a subject, including a human,having or suspected of having a disorder comprising administering to thesubject a therapeutically effective amount of a compound as disclosedherein or a pharmaceutically acceptable salt, solvate, or prodrugthereof; so as to affect a decreased metabolism via at least onepolymorphically-expressed cytochrome P₄₅₀ isoform in the subject duringthe treatment of the disease as compared to the correspondingnon-isotopically enriched compound.

Examples of polymorphically-expressed cytochrome P₄₅₀ isoforms in amammalian subject include, but are not limited to, CYP2C8, CYP2C9,CYP2C19, and CYP2D6.

In certain embodiments, the decrease in metabolism of the compound asdisclosed herein by at least one polymorphically-expressed cytochromeP₄₅₀ isoforms cytochrome P₄₅₀ isoform is greater than about 5%, greaterthan about 10%, greater than about 20%, greater than about 30%, greaterthan about 40%, or greater than about 50% as compared to thecorresponding non-isotopically enriched compound.

The metabolic activities of liver microsomes and the cytochrome P₄₅₀isoforms are measured by the methods described in Examples 41 and 42.The metabolic activities of the monoamine oxidase isoforms are measuredby the methods described in Examples 42 and 43.

Disclosed herein are methods for treating a subject, including a human,having or suspected of having a disorder comprising administering to thesubject a therapeutically effective amount of a compound as disclosedherein or a pharmaceutically acceptable salt, solvate, or prodrugthereof; so as to affect at least one statistically-significantlyimproved disorder-control and/or disorder-eradication endpoint ascompared to the corresponding non-isotopically enriched compound.Examples of improved disorder-control and/or disorder-eradicationendpoints include, but are not limited to, statistically-significantimprovement of pain indices, depression indices, and/or diminution ofhepatotoxicity, as compared to the corresponding non-isotopicallyenriched compound.

Disclosed herein are methods for treating a subject, including a human,having or suspected of having a disorder comprising administering to thesubject a therapeutically effective amount of a compound as disclosedherein or a pharmaceutically acceptable salt, solvate, or prodrugthereof; so as to affect an improved clinical effect as compared to thecorresponding non-isotopically enriched compound. Examples of improvedclinical effects include, but are not limited to,statistically-significant improvement of pain indices, perfusion ofischemic tissues with oxygen, prevention of ischemia, entheogeniceffects sufficient to facilitate psychotherapy, cataleptic effectssufficient to enable medical treatment of a non-compliant trauma victim,neuroprotection during an ischemic event, and/or diminution ofhepatotoxicity, as compared to the corresponding non-isotopicallyenriched compound.

Disclosed herein are methods for treating a subject, including a human,having or suspected of having a disorder comprising administering to thesubject a therapeutically effective amount of a compound as disclosedherein or a pharmaceutically acceptable salt, solvate, or prodrugthereof; so as to affect prevention of recurrence, or delay of declineor appearance, of abnormal alimentary or hepatic parameters as theprimary clinical benefit, as compared to the correspondingnon-isotopically enriched compound.

Disclosed herein are methods for treating a subject, including a human,having or suspected of having a disorder comprising administering to thesubject a therapeutically effective amount of a compound as disclosedherein or a pharmaceutically acceptable salt, solvate, or prodrugthereof; so as to allow the treatment while reducing or eliminatingdeleterious changes in any diagnostic hepatobiliary function endpointsas compared to the corresponding nonisotopically enriched compound.

Examples of diagnostic hepatobiliary function endpoints include, but arenot limited to, alanine aminotransferase (“ALT”), serum glutamic-pyruvictransaminase (“SGPT”), aspartate aminotransferase (“AST” or “SGOT”),ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonialevels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,” or“GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liverultrasonography, liver nuclear scan, 5′-nucleotidase, and blood protein.Hepatobiliary endpoints are compared to the stated normal levels asgiven in “Diagnostic and Laboratory Test Reference”, 4^(th) edition,Mosby, 1999. These assays are run by accredited laboratories accordingto standard protocol.

Depending on the disease to be treated and the subject's condition, thecompound of Formula I provided herein may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracistemal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topical(e.g., transdermal or local) routes of administration, and may beformulated, alone or together, in suitable dosage unit withpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration.

The dose may be in the form of one, two, three, four, five, six, or moresub-doses that are administered at appropriate intervals per day. Thedose or sub-doses can be administered in the form of dosage unitscontaining from about 0.1 to about 1000 milligram, from about 0.1 toabout 500 milligrams, or from 0.5 about to about 100 milligrams ofactive ingredient(s) per dosage unit, and if the condition of thepatient requires, the dose can, by way of alternative, be administeredas a continuous infusion.

In certain embodiments, an appropriate dosage level is about 0.01 toabout 100 mg per kg patient body weight per day (mg/kg per day), about0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, orabout 0.05 to about 10 mg/kg per day, which may be administered insingle or multiple doses. A suitable dosage level may be about 0.01 toabout 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about0.1 to about 10 mg/kg per day. Within this range the dosage may be about0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, orabout 10 to about 50 mg/kg per day.

Combination Therapy

The a compound as disclosed herein or pharmaceutically acceptable salts,solvates, or prodrugs thereof may also be combined or used incombination with other agents useful in the treatment, prevention, oramelioration of one or more symptoms of the disorders for which thecompound provided herein are useful. Or, by way of example only, thetherapeutic effectiveness of one of the compounds described herein maybe enhanced by administration of an adjuvant (i.e., by itself theadjuvant may only have minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced).

Such other agents, adjuvants, or drugs, may be administered, by a routeand in an amount commonly used therefor, simultaneously or sequentiallywith a compound as disclosed herein or a pharmaceutically acceptablesalt, solvate, or prodrug thereof. When a pharmaceutically acceptablesalt of a compound as disclosed herein is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound disclosed herein may beutilized, but is not required. Accordingly, the pharmaceuticalcompositions disclosed herein include those that also contain one ormore other active ingredients or therapeutic agents, in addition to thecompound provided herein.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more modulators of NMDA-receptors known in the art,including, but not limited to, phencyclidine (PCP), amantadine,ibogaine, memantine, dextrorphan, ketamine, nitrous oxide, anddextromethorphan.

In certain embodiments, the compounds provided herein can be combinedwith one or more natural, semisynthetic, or fully synthetic opioidsknown in the art, including, but not limited to, morphine, codeine,thebain, diacetylmorphine, oxycodone, hydrocodone, hydromorphone,oxymorphone, nicomorphine, fentanyl, α-methylfentanyl, alfentanil,sufentanil, remifentanyl, carfentanyl, ohmefentanyl, pethidine,ketobemidone, propoxyphene, dextropropoxyphene, methadone, loperamide,pentazocine, buprenorphine, etorphine, butorphanol, nalbufine,levorphanol, naloxone, naltrexone, and tramadol.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more opioid antagonists known in the art, including, but notlimited to, nalmefene, naltrexone, and naloxone.

In certain embodiments, the compounds disclosed herein can be combinedwith one or more local and/or general anesthetics and sedatives known inthe art, including, but not limited to, propofol, procaine, lidocaine,prilocaine, bupivicaine, levobupivicaine, nitrous oxide, halothane,enflurane, isoflurane, sevoflurane, desflurane, thiopental,methohexital, etomidate, diazepam, midazolam, lorazepam,succinylcholine, vecuronium, rocuronium, pipecuronium, rapacuronium,tubocurarine, and gallamine.

The compounds disclosed herein can also be administered in combinationwith other classes of compounds, including, but not limited to,endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon;thromboxane receptor antagonists, such as ifetroban; potassium channelopeners; thrombin inhibitors, such as hirudin; growth factor inhibitors,such as modulators of PDGF activity; platelet activating factor (PAF)antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g.,abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g.,clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, suchas warfarin; low molecular weight heparins, such as enoxaparin; FactorVIIa Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutralendopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACEinhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductaseinhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin,NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522(also known as rosuvastatin, or atavastatin or visastatin); squalenesynthetase inhibitors; fibrates; bile acid sequestrants, such asquestran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors;MTP Inhibitors; calcium channel blockers, such as amlodipine besylate;potassium channel activators; alpha-histamine H1 agents; beta-histamineH1 agents, such as carvedilol and metoprolol; antiarrhythmic agents;diuretics, such as chlorothlazide, hydrochiorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichioromethiazide, polythiazide, benzothlazide, ethacrynic acid,tricrynafen, chlorthalidone, furosenilde, musolimine, bumetanide,triamterene, amiloride, and spironolactone; thrombolytic agents, such astissue plasminogen activator (tPA), recombinant tPA, streptokinase,urokinase, prourokinase, and anisoylated plasminogen streptokinaseactivator complex (APSAC); anti-diabetic agents, such as biguanides(e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g. troglitazone,rosiglitazone and pioglitazone), and PPAR-gamma agonists;mineralocorticoid receptor antagonists, such as spironolactone andeplerenone; growth hormone secretagogues; aP2 inhibitors;phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil,vardenafil); protein tyrosine kinase inhibitors; antiinflammatories;antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf),mycophenolate mofetil; chemotherapeutic agents; immunosuppressants;anticancer agents and cytotoxic agents (e.g., alkylating agents, such asnitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, andtriazenes); antimetabolites, such as folate antagonists, purineanalogues, and pyrridine analogues; antibiotics, such as anthracyclines,bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such asL-asparaginase; farnesyl-protein transferase inhibitors; hormonalagents, such as glucocorticoids (e.g., cortisone),estrogens/antiestrogens, androgens/antiandrogens, progestins, andluteinizing hormone-releasing hormone antagonists, and octreotideacetate; microtubule-disruptor agents, such as ecteinascidins;microtubule-stablizing agents, such as pacitaxel, docetaxel, andepothilones A-F; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;prenyl-protein transferase inhibitors; and cyclosporins; steroids, suchas prednisone and dexamethasone; cytotoxic drugs, such as azathiprineand cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNFantibodies or soluble TNF receptor, such as etanercept, rapamycin, andleflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxiband rofecoxib; and miscellaneous agents such as, hydroxyurea,procarbazine, mitotane, hexamethylmelamine, gold compounds, platinumcoordination complexes, such as cisplatin, satraplatin, and carboplatin.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) comprising one of the separate elements to be usedin a method described herein.

For example, the container(s) can comprise one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an

intravenous solution bag or a vial having a stopper pierceable by ahypodermic injection needle). Such kits optionally comprise a compoundwith an identifying description or label or instructions relating to itsuse in the methods described herein.

A kit will typically comprise one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but are not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label or package insert can be on, in, or associated with thecontainer. A label can be used to indicate that the contents are to beused for a specific therapeutic application. The label can also indicatedirections for use of the contents, such as in the methods describedherein. These other therapeutic agents may be used, for example, in theamounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

As used herein, and unless otherwise indicated, the followingabbreviations have the following meanings: Me refers to methyl (CH₃—),Et refers to ethyl (CH₃CH₂—), i-Pr refers to isopropyl ((CH₃)₂CH₂—),t-Bu or tert-butyl refers to tertiary butyl ((CH₃)₃CH—), Ph refers tophenyl, Bn refers to benzyl (PhCH₂—), Bz refers to benzoyl (PhCO—), MOMrefers to methoxymethyl, Ac refers to acetyl, TMS refers totrimethylsilyl, TBS refers to tert-butyldimethylsilyl, Ms refers tomethanesulfonyl (CH₃SO₂—), Ts refers to p-toluenesulfonyl (p-CH₃PhSO₂—),Tf refers to trifluoromethanesulfonyl (CF₃SO₂—), TfO refers totrifluoromethanesulfonate (CF₃SO₃—), D₂O refers to deuterium oxide, DMFrefers to N,N-dimethylformamide, DCM refers to dichloromethane (CH₂Cl₂),THF refers to tetrahydrofuran, EtOAc refers to ethyl acetate, Et₂Orefers to diethyl ether, MeCN refers to acetonitrile (CH₃CN), NMP refersto 1-N-methyl-2-pyrrolidinone, DMA refers to N,N-dimethylacetamide, DMSOrefers to dimethylsulfoxide, DCC refers to1,3-dicyclohexyldicarbodiimide, EDCI refers to1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Boc refers totert-butylcarbonyl, Fmoc refers to 9-fluorenylmethoxycarbonyl, TBAFrefers to tetrabutylammonium fluoride, TBAI refers to tetrabutylammoniumiodide, TMEDA refers to N,N,N,N-tetramethylethylene diamine, Dess-Martinperiodinane or Dess Martin reagent refers to1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, DMAP refers to4-N,N-dimethylaminopyridine, (i-Pr)₂NEt or DIEA or Hunig's base refersto N,N-diethylisopropylamine, DBU refers to1,8-Diazabicyclo[5.4.0]undec-7-ene, (DHQ)₂AQN refers to dihydroquinineanthraquinone-1,4-diyl diether, (DHQ)₂PHAL refers to dihydroquininephthalazine-1,4-diyl diether, (DHQ)₂PYR refers to dihydroquinine2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQD)₂AQN refers todihydroquinidine anthraquinone-1,4-diyl diether, (DHQD)₂PHAL refers todihydroquinidine phthalazine-1,4-diyl diether, (DHQD)₂PYR refers todihydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether, LDA refers tolithium diisopropylamide, LiTMP refers to lithium2,2,6,6-tetramethylpiperdinamide, n-BuLi refers to n-butyl lithium,t-BuLi refers to tert-butyl lithium, IBA refers to1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide, OsO₄ refers to osmiumtetroxide, m-CPBA refers to meta-chloroperbenzoic acid, DMD refers todimethyl dioxirane, PDC refers to pyridinium dichromate, NMO refers toN-methyl morpholine-N-oxide, NaHMDS refers to sodiumhexamethyldisilazide, LiHMDS refers to lithium hexamethyldisilazide,HMPA refers to hexamethylphosphoramide, TMSCl refers to trimethylsilylchloride, TMSCN refers to trimethylsilyl cyanide, TBSCl refers totert-butyldimethylsilyl chloride, TFA refers to trifluoroacetic acid,TFAA refers to trifluoroacetic anhydride, AcOH refers to acetic acid,Ac₂O refers to acetic anhydride, AcCl refers to acetyl chloride, TsOHrefers to p-toluenesulfonic acid, TsCl refers to p-toluenesulfonylchloride, MBHA refers to 4-methylbenzhydrylamine, BHA refers tobenzhydrylamine, ZnCl₂ refers to zinc (II) dichloride, BF₃ refers toboron trifluoride, Y(OTf)₂ refers to yttrium (III)trifluoromethanesulfonate, Cu(BF₄)₂ refers to copper (II)tetrafluoroborate, LAH refers to lithium aluminum hydride (LiA₁H₄), LADrefers to lithium aluminum deuteride, NaHCO₃ refers to Sodiumbicarbonate, K₂CO₃ refers to Potassium carbonate, NaOH refers to sodiumhydroxide, KOH refers to potassium hydroxide, LiOH refers to lithiumhydroxide, HCl refers to hydrochloric acid, H₂SO₄ refers to sulfuricacid, MgSO₄ refers to magnesium sulfate, and Na₂SO₄ refers to sodiumsulfate. ¹H NMR refers to proton nuclear magnetic resonance, ¹³C NMRrefers to carbon-13 nuclear magnetic resonance, NOE refers to nuclearoverhauser effect, NOESY refers to nuclear overhauser and exchangespectroscopy, COSY refers to homonuclear correlation spectroscopy, HMQCrefers to proton detected heteronuclear multiplet-quantum coherence,HMBC refers to heteronuclear multiple-bond connectivity, s refers tosinglet, br s refers to broad singlet, d refers to doublet, br d refersto broad doublet, t refers to triplet, q refers to quartet, dd refers todouble doublet, m refers to multiplet, ppm refers to parts per million,IR refers to infrared spectrometry, MS refers to mass spectrometry, HRMSrefers to high resolution mass spectrometry, EI refers to electronimpact, FAB refers to fast atom bombardment, CI refers to chemicalionization, HPLC refers to high pressure liquid chromatography, TLCrefer to thin layer chromatography, Rf refers to retention factor, Rtrefers to retention time, GC refers to gas chromatography, min isminutes, h is hours, rt or RT is room or ambient temperature, g isgrams, mg is milligrams, kg is kilograms, L is liters, mL ismilliliters, mol is moles and mmol is millimoles.

The invention is further illustrated by the following examples.

EXAMPLES Example 1—d₉-2-(4-Methoxyphenyl)-acetic acid

d₉-(4-Methoxyphenyl)-acetic acid can be prepared according to knownliterature procedures Ouk et al., Green Chemistry, 2002, 4(5), 431-435,which is hereby incorporated by reference in its entirety, by reactingd₆-(4-hydroxyphenyl)-acetic acid (1 equiv, Cambridge IsotopesLaboratories), K₂CO₃ (0.04 equiv) and d₆-carbonic acid dimethyl ester(1.25 equiv, Cambridge Isotopes Laboratories) at 160° C. untilcompletion.

Example 2—d₁₅-2-(4-Methoxyphenyl)-N,N-dimethyl-acetamide

The title compound is prepared according to the procedure described inYardley et al, Journal of Medicinal Chemistry 1990, 33(10), 2899-2905,which is hereby incorporated by reference in its entirety. A solution ofd₉-(4-methoxyphenyl)-acetic acid (1 equiv) in methylene chloride istreated with oxalyl chloride (1.22 equiv) and DMF (catalytic amount) andthen stirred at room temperature until all acid is converted to the acidchloride. The solvent is removed under reduced pressure and the residueis taken up in methylene chloride and treated with d₆-dimethylaminehydrochloride (1 equiv, Cambridge Isotopes Laboratories), ethyldiisopropylamine (2.1 equiv), and DMAP (0.2 equiv). The mixture isstirred overnight, the solvent is removed under reduced pressure and thecrude residue is purified by silica gel column chromatography.

Example3—d₂₄-2-(1-Hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethyl-acetamide

The title compound is prepared according to the procedure described inYardley et al., Journal of Medicinal Chemistry 1990, 33(10), 2899-2905,which is hereby incorporated by reference in its entirety. A solution ofd₁₅-2-(4-methoxyphenyl)-N,N-dimethylacetamide (1 equiv) in THF istreated with n-butyllithium (1 equiv) at −78° C. The mixture is stirredfor 90 minutes at −78° C.; a THF solution of d₁₀-cyclohexanone (1.2equiv, Sigma-Aldrich) is added, and stirring is maintained untilcompletion. The reaction is quenched by addition of D₂O (2 equiv), themixture is warmed to room temperature and the solvent is removed underreduced pressure and the crude residue is purified by silica gel columnchromatography.

Example 4—d₂₆-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol

The title compound is prepared according to the procedure described inYardley et al., Journal of Medicinal Chemistry 1990, 33(10), 2899-2905,which is hereby incorporated by reference in its entirety.d₂₄-2-(1-Hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethylacetamide (1equiv) in THF is added dropwise to a mixture of lithium aluminumdeuteride (1.6 equiv) at 0° C. and stirred until completion. Thereaction is quenched with D₂O, and worked up under standard conditionsknown to one skilled in the art. The mixture is then filtered and theprecipitate is washed several times with THF. The combined filtrates areevaporated, and the residue is recrystallized from a suitable solvent.

Example 5—d₃-(4-Methoxyphenyl)-acetonitrile

d₃-Iodomethane (8.70 g, 60 mmol) was added to a stirred solution of(4-hydroxyphenyl)-acetonitrile (4.50 g, 30 mmol) in acetone (30 mL)containing potassium carbonate (6.21 g, 45 mmol) at ambient temperature,and the mixture was heated at reflux overnight, cooled to ambienttemperature, filtered, and concentrated to give the crude product, whichwas purified by flash chromatography using hexanes-ethyl acetate toafford the desired product, d₃-(4-methoxyphenyl)-acetonitrile, as alight yellow oil.

Yield: 3.99 g (89%). ¹H-NMR (CDCl₃) δ ppm: 3.67 (s, 2H), 6.88 (d, 2H,J=8.7 Hz), 7.22 (d, 2H, J=8.7 Hz).

Example 6—d₃-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile

Tetra-n-butyl ammonium hydrogen sulfate (0.10 g, 0.29 mmol) and 2N NaOH(1.2 mL) were added sequentially to a vigorously stirredd₃-(4-methoxyphenyl)-acetonitrile (0.85 g, 5.66 mmol) at 0° C., andstirring was maintained for 30 minutes. Cyclohexanone (0.67 g, 6.8 mmol)was added to this mixture at 0-5° C. over 10 minute. The reactionmixture was allowed to warm to ambient temperature and vigorous stirringwas continued for an additional 1 hour. The white precipitate wasfiltered and washed with water and hexanes to afford the desiredproduct, d₃-(1-hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile, as awhite solid.

Yield: 1.28 g (91%). ¹H-NMR (CDCl₃) δ ppm: 1.05-1.80 (m, 10H), 3.73 (s,1H), 6.90 (d, 2H, J=8.7 Hz), 7.27 (d, 2H, J=8.7 Hz).

Example 7—d₃-1-[2-Amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol

d₃-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile (400.0 mg, 1.61mmol) was reduced on an H-Cube™ continuous-flow hydrogenation reactor(Thales Nanotechnology, Budapest, Hungary) equipped with a Raney Nicatalyst cartridge (eluent: 2.0M ammonia in methanol, flow rate: 1mL/min, temperature: 80° C., pressure: 80 bar) to yield the desiredproduct, d₃-1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, as aclear colorless oil.

Yield: 280 mg (69%). ¹H-NMR (CDCl₃) δ ppm: 1.05-1.80 (m, 10H), 2.59 (brs, 2H), 2.68 (t, 1H, 6.9 Hz), 3.21 (m, 2H), 6.83 (d, 2H, J=9.0 Hz), 7.17(d, 2H, J=9.0 Hz).

Example8—d₁₂-1-[2-Trimethylammonium-1-(4-methoxyphenyl)-ethyl]-cyclohexanolIodide

D₃-Iodomethane (0.4 mL, 6.34 mmol) and potassium carbonate (424 mg, 3.0mmol) were added at ambient temperature to a solution of d₃1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol (252 mg, 1.0 mmol) inanhydrous tetrahydrofuran (1.5 ml.), and stirred at ambient temperaturefor 20 hours. The reaction mixture was diluted with tetrahydrofuran,filtered, and the filtrate was concentrated in vacuo to provide theproduct,d₁₂-1-[2-trimethylammonium-1-(4-methoxyphenyl)-ethyl]-cyclohexanoliodide, as a beige solid. ¹H-NMR (CD₃OD) δ ppm: 0.90-1.80 (m, 10H), 3.19(m, 1H), 4.00 (m, 2H), 6.93 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H).

Example 9—d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₉-venlafaxine)

A solution ofd₁₂-1-[2-trimethylammonium-1-(4-methoxyphenyl)-ethyl]-cyclohexanoliodide in 3-amino-1-propanol (1 mL) was heated at 170° C. for 4 hours,cooled to ambient temperature, diluted with water and extracted withethyl acetate. The combined organic layers were washed with brine, driedand concentrated under reduced pressure. The resulting residue wasdissolved in 6N hydrochloric acid (5 ml.), washed with ether. Theaqueous layer was basified with 30% aqueous sodium hydroxide to pH=11-12and extracted with ethyl acetate. The organic extract was washed withbrine, dried, and concentrated to afford d₉-venlafaxine (208 mg, 73%).¹H-NMR (CDCl₃) δ ppm: 0.78-1.80 (m, 10H), 2.33 (dd, 1H, J=12.0, 3.3 Hz),2.96 (dd, 1H, J=12.0, 3.3 Hz), 3.31 (t, 1H, J=12.0 Hz), 6.81 (d, 2H,J=9.0 Hz), 7.17 (d, 2H, J=9.0 Hz). MS (m/z): 287 (M+1).

Example 10—d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₉-venlafaxine hydrochloride)

A solution of d₉-venlafaxine (63 mg, 0.22 mmol) in ether (10 mL) wastreated with 2N hydrochloric acid in ether (0.2 mL) at 0° C. for 10minutes. The white precipitate was collected by filtration, washed withether, and dried in vacuo to provide d₉-venlafaxine hydrochloride salt(60 mg, 85%). 1H-NMR (CD₃OD) δ ppm: 0.95-1.80 (m, 10H), 2.83 (s, 6H),3.04 (dd, 1H, J=9.9, 5.4 Hz), 3.68 (m, 2H), 6.96 (d, 2H, J=9.0 Hz), 7.30(d, 1H, J=9.0 Hz).

Example11—d₃-1-[2-Trimethylammonium-1-(4-methoxyphenyl)-ethyl]-cyclohexanolIodide

Prepared according to Example 8 by substituting methyl iodide ford₃-methyl iodide. 1H-NMR (CD₃OD) δ ppm: 0.90-1.80 (m, 10H), 3.05 (s,9H), 3.12 (m, 1H), 3.96 (m, 2H), 6.94 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1Hz, 2H).

Example 12—d₃-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₃-venlafaxine)

Prepared according to Example 9. 1H-NMR (CD₃OD) δ ppm: 0.84-1.54 (m,10H), 2.42 (s, 6H), 2.84-2.92 (m, 2H), 3.26-3.36 (m, 1H), 6.87 (d, 2H),7.18 (d, 2H).

Example 13—d₃-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₃-venlafaxine hydrochloride)

Prepared according to Example 10.

Example 14—d₃-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₃-venlafaxine)

d₃-1-[2-Amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol (207 mg, 0.82mmol), 37% aqueous formaldehyde (0.3 mL), formic acid (0.3 mL) and water(2 mL) were stirred at 80-90° C. for 12 hours, concentrated in vacuo toa volume of 1.5 mL, made basic by the dropwise addition of aqueous 20%sodium hydroxide, and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered and concentratedin vacuo to give a crude residue which was purified by silica gelchromatography (ethyl acetate-methanol-ammonium hydroxide) to give thedesired product,d₃-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol.

Yield: 24.4 mg (11%). ¹H-NMR (methanol-d₄) δ ppm: 0.84-1.54 (m, 10H),2.42 (s, 6H), 2.84-2.92 (m, 2H), 3.26-3.36 (m, 1H), 6.87 (d, 2H), 7.18(d, 2H).

Example 15—d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₉-venlafaxine)

A solution of d₃-1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(0.126 g, 0.5 mmol), d₂-formic acid (0.3 mL), and d₂-formaldehyde (20 wt% in D₂O, 0.25 mL) in D₂O (1.5 mL) was heated at 100° C. for 16 hours,cooled to ambient temperature, diluted with water (5 mL), neutralizedwith 35% aqueous ammonia, and extracted with ethyl acetate. The combinedorganic layers were dried over sodium sulfate and concentrated underreduced pressure to yield a crude residue which was purified by flashchromatography (ethyl acetate-methanol-NH₄OH) to give the desiredproduct, d₉-1-[2-methylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, asa light yellow semi-solid.

Yield: 0.024 g (20%). ¹H-NMR (CDCl₃) δ ppm: 0.78-1.80 (m, 10H), 2.33(dd, 1H, J=12.0, 3.3 Hz), 2.96 (dd, 1H, J=12.0, 3.3 Hz), 3.31 (t, 1H,J=12.0 Hz), 6.81 (d, 2H, J=9.0 Hz), 7.17 (d, 2H, J=9.0 Hz). MS (m/z):287 (M+1).

Example 16—d₁₄-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile

The title compound was prepared as in Example 6 by substitutingd₁₀-cyclohexanone (Sigma-Aldrich) for cyclohexanone and 2N NaOD in D₂Ofor 2N NaOH in water. The final product was purified byrecrystallization from ethyl acetate-hexanes.

Yield (60%). ¹H-NMR (CDCl₃) δ ppm: 1.60 (br s, 1H), 6.90 (d, 2H, J=8.4Hz), 7.26 (d, 2H, J=8.4 Hz).

Example 17—d₁₄-1-[2-Amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol

d₁₄-(1-Hydroxycyclohexyl)-(4-methoxyphenyl)-acetonitrile (570.0 mg, 2.21mmol) was reduced on an H-Cube™ continuous-flow hydrogenation reactor(Thales Nanotechnology, Budapest, Hungary) equipped with a Raney Nicatalyst cartridge (eluent: 2.0M ammonia in methanol, flow rate: 1mL/min, temperature: 80° C., pressure: 80 bar) to yield the desiredproduct, d₁₄-1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, as aclear colorless oil.

Yield: 530 mg (92%). ¹H-NMR (CDCl₃) δ ppm: 2.62 (br s, 3H), 3.21 (dd,2H), 6.83 (d, 2H), 7.17 (d, 2H).

Example18—d₁₄-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₁₄-venlafaxine)

A solution of d₁₄-1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(257.0 mg, 0.98 mmol), formic acid (0.334 mL), and formaldehyde (37% inwater, 0.146 mL) in water (2.32 mL) was stirred at room temperature for45 minutes. Formaldehyde (37% in water, 0.146 mL) was added and themixture was heated to reflux for 17 hours, cooled to room temperature,washed with ethyl acetate, made basic with 20% aqueous sodium hydroxideand extracted with ethyl acetate. The combined organic fractions werewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo togive a crude residue which was purified by column chromatography (ethylacetate-methanol-ammonium hydroxide) to give the desired product,d₁₄-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, as aclear colorless oil.

Yield: 154.4 mg (54%), ¹H-NMR (methanol-d₄) δ ppm: 2.25 (s, 6H), 2.55(d, 1H), 3.14 (d, 1H), 6.84 (d, 2H), 7.13 (d, 2H).

Example19—d₂₀-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₂₀-venlafaxine)

The title compound was prepared as in Example 15.

Yield (31%). ¹H-NMR (CDCl₃) δ ppm: 2.33 (d, 1H, J=12.6 Hz), 3.30 (d, 1H,J=12.6 Hz), 6.81 (d, 2H, J=9.0 Hz), 7.05 (d, 2H, J=9.0 Hz). MS (m/z):298 (M+1).

Example 20—d₆-4-[2-Dimethylamino-1-(1-hydroxycyclohexyl)-ethyl]-phenol(d₆-O-desmethylvenlafaxine)

A 1.0 M solution of boron tribromide in methylene chloride (0.125 mL,0.125 mol) was added at −40° C. to a stirred solution of d₉-venlafaxine(17 mg, 0.059 mmol) in methylene chloride (0.5 mL) over 5 minutes, andthe mixture was allowed to warm to 0° C. over 30 minutes. After beingstirred for additional 3 hours at 0° C., the reaction was quenched at 0°C. with aqueous 2N NaOH (0.35 mL) and the mixture was slowly allowed towarm to ambient temperature overnight with stirring. The solvent wasremoved under reduced pressure and the resulting residue was extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over sodium sulfate, filtered, and concentrated in vacuo to givethe title compound as a beige solid.

Yield: 75%. ¹H-NMR (CDCl₃) δ: 0.75-1.80 (m, 10H), 2.52 (dd, 1H, J=12.3,4.2 Hz), 2.99 (dd, 1H, J=10.2, 4.2 Hz), 3.39 (t, 1H, J=10.8 Hz), 6.75(d, 2H, J=8.7 Hz), 6.99 (d, 1H, J=8.7 Hz). MS: m/z 270.1 (M⁺+1).

Example 21—d₁₁-4-[2-Dimethylamino-1-(1-hydroxycyclohexyl)-ethyl]-phenol(d₁₁-O-desmethylvenlafaxine)

The title compound is prepared from d₁₄-venlafaxine according to Example20.

Example 22—d₂₃-4-[2-Dimethylamino-1-(1-hydroxycyclohexyl)-ethyl]-phenol(d₂₃-O-desmethylvenlafaxine)

The title compound is prepared from d₂₆-venlafaxine according to Example20.

Example23—(S)-d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolHydrochloride Salt ((S)-d₉-venlafaxine HCl)

A solution of (−)-di-p-toluoyl-L-tartaric acid (3.60 mmol) in ethylacetate (10 mL) was added at once at room temperature to a solution ofd₉-venlafaxine (7.22 mmol) in ethyl acetate (20 mL), and the mixture wasstirred at room temperature for 4 hours. The resulting precipitate wascollected by filtration, dried and recrystallized from a mixture ofmethanol and ethyl acetate to afford d₉-(S)-venlafaxine di-p-toluoyl-Ltartarate salt as white crystals (optical purity >99.5% by a chiralHPLC). The filtrate was used to provide d₉-(R)-venlafaxine (see Example18). Chiral separation was performed at ambient temperature on anAgilent 1100 HPLC equipped with a Chirobiotic V chiral column (Astec),250×4.6 mm column. Isocratic gradient: 5 mM ammonium acetate in water(60%) and tetrahydrofuran (40%); Flowrate: 1 mL/min; Run time: 30minutes; Injection volume: 10 μL injection (1 mg/mL). UV wavelength: 229nm. All samples were dissolved in acetonitrile-water (1:1).

d₉-(S)-venlafaxine di-p-toluoyl-L tartarate salt was suspended indichloromethane (25 mL) and treated with 2N NaOH until pH 13. The layerswere separated and the aqueous layer was extracted with dichloromethane.The combined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated to give d₉-(S)-venlafaxine as awhite solid Yield: 0.71 g. ¹H-NMR (CDCl₃) δ: 0.75-1.80 (m, 10H), 2.37(s, 6H), 2.40 (m, 1H), 3.01 (dd, 1H, J=11.1, 3.3 Hz), 3.39 (t, 1H,J=12.0 Hz), 6.81 (d, 2H, J=8.7 Hz), 7.05 (d, 1H, J=8.7 Hz). MS: m/z281.3 (M⁺+1).

d₉-(S)-venlafaxine (0.69 g, 2.46 mol) was dissolved in ether (30 mL) andtreated with a solution of 2N HCl in ether (1.7 mL) at 0-5° C. for 10minutes. The precipitate was filtered, washed with ether, andrecrystallized from a mixture of ether and methanol to gived₉-(S)-venlafaxine HCl salt as a white solid (optical purity >99.5% bychiral HPLC).

Yield: 0.55 g. ¹H-NMR (CD₃OD) δ: 0.95-1.80 (m, 10H), 2.83 (s, 6H), 3.04(dd, 1H, J=9.9, 5.4 Hz), 3.68 (m, 2H), 6.96 (d, 2H, J=9.0 Hz), 7.30 (d,1H, J=9.0 Hz). Chiral HPLC: RT=23.45 min.

Example24—(R)-d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolHydrochloride Salt ((R)-d₉-venlafaxine HCl)

The filtrate obtained in Example 23 was concentrated under reducedpressure, and the resulting residue (1.80 g) was dissolved indichloromethane and treated with 2N aqueous sodium hydroxide as inExample 23, washed with brine, and concentrated to give a white solid(1.01 g), which was dissolved in ethyl acetate (15 mL) and treated with(+)-di-p-toluoyl-D-tartaric acid in ethyl acetate (10 mL). The mixturewas stirred at room temperature for 4 hours. The resulting whiteprecipitate was collected by filtration and recrystallized from amixture of ethyl acetate and methanol to provide d₉-(R)-venlafaxinedi-p-toluoyl-D tartarate salt (optical purity >99.5% by chiral HPLC).The corresponding free base of d₉-(R)-venlafaxine (optical purity >99.5%by chiral HPLC) were prepared as in Example 23.

Example25—(S)-d₃-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride ((S)-d₃-venlafaxine HCl)

Prepared according to Example 23.

Example26—(R)-d₃-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride ((R)-d₃-venlafaxine HCl)

Prepared according to Example 23.

Example27—(18-5-(4-Methoxy-phenyl)-3-methyl-1-oxa-3-aza-spiro[5.5]undecane

A solution of d₃-1-[2-amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(0.126 g, 0.5 mmol), d₂ formic acid (0.3 mL), and d₂-formaldehyde (20 wt% in deuterium oxide, 0.25 mL) in deuterium oxide (1.5 mL) was heated at100° C. for 16 hours, cooled to ambient temperature, diluted with water(5 mL), neutralized with 35% aqueous ammonia, and extracted with ethylacetate. The combined organic layers were dried over sodium sulfate andconcentrated under reduced pressure to yield a crude residue which waspurified by flash chromatography (ethyl acetate-methanol-ammoniumhydroxide) to give the desired product,d₈-5-(4-methoxyphenyl)-3-methyl-1-oxa-3-aza-spiro[5.5]undecane. ¹H-NMR(CDCl₃) δ: 0.75-1.80 (m, 9H), 2.28 (br d, 1H), 2.70 (dd, 1H, J=12.3, 3.6Hz), 3.03 (dd, 1H, J=12.3, 3.6 Hz), 3.21 (t, 1H, J=12.3 Hz), 6.81 (d,2H, J=8.7 Hz), 7.05 (d, 2H, J=8.7 Hz). MS: m/z 284 (M+1).

Example 28—d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₉-venlafaxine)

A stirred emulsion ofd₈-5-(4-methoxyphenyl)-3-methyl-1-oxa-3-aza-spiro[5.5]undecane (1.93 g,6.82 mmol) in deuterium oxide (25 mL) was treated with d₂-formic acid(1.96 g, 40.92 mmol), and 30% sodium deuteroxide in deuterium oxide (2.8mL, 20.46 mmol) at ambient temperature. The resulting clear solution washeated at 100° C. for 20 hours, cooled to ambient temperature, dilutedwith water, basified to pH=11 with 2N aqueous sodium hydroxide, andextracted with ethyl acetate. The combined organic extracts were driedand concentrated under reduced pressure to give a crude residue, whichwas purified by flash column chromatography to afford d₉-venlafaxine(1.21 g, 62%) as a white solid.

Example 29—d₈-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol(d₈-venlafaxine)

A stirred emulsion ofd₈-5-(4-methoxyphenyl)-3-methyl-1-oxa-3-aza-spiro[5.5]undecane (123 mg,0.434 mmol) in water (1 mL) was treated with formic acid (100 mg, 2.17mmol), and sodium formate at 100° C. for 18 hours, cooled to ambienttemperature, diluted with water, basified to pH=11 with 2N aqueoussodium hydroxide, and extracted with ethyl acetate. The combined organicextracts were dried and concentrated under reduced pressure to give acrude residue, which was purified by flash column chromatography toafford d₈-venlafaxine (68 mg, 55%) as a white solid. ¹H-NMR (CDCl₃) δ:0.75-1.80 (m, 10H), 2.28 (s, 1H), 2.32 (dd, 1H, J=12.3, 3.3 Hz), 2.96(dd, 1H, J=12.3, 3.3 Hz), 3.31 (t, 1H, J=12.3 Hz), 6.81 (d, 2H, J=8.7Hz), 7.05 (d, 2H, J=8.7 Hz). MS: m/z 286.4 (M+1).

Example 30—d₈-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride (d₈-venlafaxine hydrochloride)

Prepared according to Example 23. ¹H-NMR (CD₃OD) δ: 0.85-1.80 (m, 10H),2.80 (s, 1H), 3.04 (dd, 1H, J=9.9, 5.4 Hz), 3.59-3.75 (m, 2H), 6.96 (d,2H, J=8.4 Hz), 7.30 (d, 2H, J=8.4 Hz).

Example 31—d₅-1-[2-Amino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol

The title compound can be prepared according to the procedure of Example7, by substituting the water reservoir with a deuterium oxide reservoirfor the generation of deuterium gas.

Example32—(R)-d₆-4-[2-Dimethylamino-1-(1-hydroxycyclohexyl)-ethyl]-phenol((R)-d₆-O-desmethylvenlafaxine)

The title compound was prepared from (R)-d₉-venlafaxine according toExample 20.

Example33—(S)-d₆-4-[2-Dimethylamino-1-(1-hydroxycyclohexyl)-ethyl]-phenol((S)-d₆-O-desmethylvenlafaxine)

The title compound was prepared from (S)-d₉-venlafaxine according toExample 20.

Example 34 d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride Form A (d₉-venlafaxine hydrochloride Form A)

d₉-Venlafaxine hydrochloride (500 mg) was dissolved in isopropanol (8mL) at about 60° C., and subsequently cooled to 0-5° C. in ice-waterbath and kept at that temperature for about 3 hours. The solid wasfiltered, washed with cold isopropanol and dried under high vacuum togive d₉-venlafaxine hydrochloride Form A (248 mg). Characteristic X-raypowder diffraction peaks (2-theta, [% relative intensity]): 6.703[29.3], 8.321 [19], 12.681 [77.5], 13.5 [47.9], 15.54 [17.7], 18.918[24.4], 20.359 [100], 21.161 [38.3], 21.762 [26.1], 25.04 [27.8], 28.518[18.2], and 35.181 [15.5]. A sample of d₉-venlafaxine hydrochloride FormA was analyzed by infrared spectroscopy. The results are shown in FIG.7.

Example 35—d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride Form B (d₉-venlafaxine hydrochloride Form B)

d₉-Venlafaxine hydrochloride (150 mg) was triturated in a vial withacetone at about 60° C. for about 1 hour and cooled to 0-5° C. for about1 hour. The solid was filtered, washed with cold acetone and dried at50° C. on rotary evaporator to a constant weight to give ds-venlafaxinehydrochloride Form B (102 mg). Characteristic X-ray powder diffractionpeaks (2-theta, [% relative intensity)): 6.683 [15.5], 10.201 [93.6],13.441 [27.8], 15.517 [66.2], 18.198 [41], 19.719 [34.1], 20.258 [100],21.68 [71.2], 22.658 [24.8], 25.543 [22.4], 28.022 [20.9], and 35.02[33.4]. A sample of d₉-venlafaxine hydrochloride Form B was analyzed byinfrared spectroscopy. The results are shown in FIG. 8. A sample ofd₉-venlafaxine hydrochloride Form B was heated at 10° C./min fromambient to approximately 700° C. and then in regular mode to 1000° C.,in a nitrogen atmosphere (25 cc/min). The results are shown in FIG. 13.

Example 36—d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride Form C (d₉-venlafaxine hydrochloride Form C)

A slurry of d₉-venlafaxine hydrochloride Form A (70 mg) in isopropanol(0.56 mL) was stirred in a vial at ambient temperature for 3 days. Thesolid was filtered, washed with cold isopropanol and dried under highvacuum to give d₉-venlafaxine hydrochloride Form C (30 mg).Characteristic X-ray powder diffraction peaks (2-theta, [% relativeintensity]): 6.718 [21.4], 8.335 [20.6], 12.68 [80], 13.5 [40.7], 15.539[20.2], 16.282 [24.3], 18.902 [48.9], 19.737 [17.4], 20.34 [100], 21.161[79.4], 21.758 [30.5], 25.601 [18.9], 26.261 [15.2], 28.518 [30.2],31.54 [18.7], 33.937 [16.5], and 35.159 [21.3]. A sample ofd₉-venlafaxine hydrochloride Form C was analyzed by infraredspectroscopy. The results are shown in FIG. 9. A sample ofd₉-venlafaxine hydrochloride Form C was heated at 10° C./min fromambient to approximately 700° C. and then in regular mode to 1000° C.,in a nitrogen atmosphere (25 cc/min). The results are shown in FIG. 14.

Example 37—d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride Form D (d₉-venlafaxine hydrochloride Form D)

A suspension of d₉-venlafaxine hydrochloride (1.45 g) in ether (40 mL)was heated under reflux at 65° C. Methanol was added dropwise to themixture until it became homogeneous and the solution was cooled toambient temperature, and kept at that temperature for 1 hour and at 0-5°C. for an additional 3 hours. The solid was filtered and dried underhigh vacuum to provide d₉-venlafaxine hydrochloride Form D (1.08 g).Characteristic X-ray powder diffraction peaks (2-theta, [% relativeintensity]): 6.74 [21.2], 7.421 [14], 8.341 [35.5], 10.219 [23], 12.7[99.5], 13.502 [40.7], 17.9 [17.5], 15.541 [37.3], 20.36 [100], 21.221[23.7], 21.761 [41], 25.078 [26.3], 31.04 [17.7], and 35.139 [22.7]. Asample of d₉-venlafaxine hydrochloride Form D was analyzed by infraredspectroscopy. The results are shown in FIG. 10.

Example 38—d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride Form E (d₉-venlafaxine hydrochloride Form E)

d₉-Venlafaxine hydrochloride Form D (98 mg) was heated in a sealed tubefor 1.5 hours at 200-200° C. and cooled to ambient temperature.Characteristic X-ray powder diffraction peaks (2-theta, [% relativeintensity]): 5.597 [28], 7.182 [36.2], 9.078 [24.1], 9.557 [14.9],11.201 [100], 14.46 [40.2], 14.76 [40.4], 16.86 [71.7], 17.497 [15.7],19.201 [66.5], 19.619 [19.6], 20.241 [35.2], 20.66 [19.6], 21.76 [22.5],22.596 [26.4], 23.06 [13.2], 24.4 [15.3], 26.842 [18.7], 31.52 [12.6],and 35.438 [17.9]. A sample of d₉-venlafaxine hydrochloride Form E wasanalyzed by infrared spectroscopy. The results are shown in FIG. 11. Asample of d₉-venlafaxine hydrochloride Form E was heated at 10° C./minfrom ambient to approximately 700° C. and then in regular mode to 1000°C., in a nitrogen atmosphere (25 cc/min). The results are shown in FIG.15.

Example 39 d₉-1-[2-Dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanolhydrochloride Form F (d₉-venlafaxine hydrochloride Form F)

d₉-Venlafaxine hydrochloride Form A (68 mg) was heated at 205° C. for 2hours and cooled to ambient temperature. The crystals that formed at thetop of the flask were collected. Characteristic X-ray powder diffractionpeaks (2-theta, [% relative intensity]): 5.581 [26.1], 7.186 [18.3],11.22 [100], 14.499 [18.8], 14.802 [20.5], 16.882 [63.9], 19.242 [38.4],20.317 [51.6], 21.798 [17.5], 22.637 [26.3], and 35.445 [16.2]. A sampleof d₉-venlafaxine hydrochloride Form F was analyzed by infraredspectroscopy. The results are shown in FIG. 12.

Example 40—In Vitro Liver Microsomal Stability Assay

Liver microsomal stability assays were conducted at 1 mg per mL livermicrosome protein with an NADPH-generating system in 2% NaHCO₃ (2.2 mMNADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphatedehydrogenase and 3.3 mM MgCl₂). Test compounds were prepared assolutions in 20% acetonitrile-water and added to the assay mixture(final assay concentration 5 microgram per mL) and incubated at 37° C.Final concentration of acetonitrile in the assay were <1%. Aliquots (50μL) were taken out at times 0, 15, 30, 45, and 60 minutes, and dilutedwith ice cold acetonitrile (200 μL) to stop the reactions. Samples werecentrifuged at 12000 RPM for 10 minutes to precipitate proteins.Supernatants were transferred to microcentrifuge tubes and stored forLC/MS/MS analysis of the degradation half-life of the test compounds. Ithas thus been found that the compounds as disclosed herein that havebeen tested in this assay showed an increase of 10% or more in thedegradation half-life, as compared to the non-isotopically enricheddrug. For example, the degradation half-life of (±)-d₃-venlafaxine,(R)-d₃-venlafaxine, (S)-d₃-venlafaxine, (±)-d₈-venlafaxine,(±)-d₉-venlafaxine, (R)-d₉-venlafaxine, (S)-d₉-venlafaxine,d₁₄-venlafaxine, and d₂₀-venlafaxine were increased by 50-300% ascompared to non-isotopically enriched venlafaxine.

Example 41—In Vitro Metabolism Using Human Cytochrome P₄₅₀ Enzymes

The cytochrome P₄₅₀ enzymes are expressed from the corresponding humancDNA using a baculovirus expression system (BD Biosciences). A 0.25milliliter reaction mixture containing 0.8 milligrams per milliliterprotein, 1.3 millimolar NADP⁺, 3.3 millimolar glucose-6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesiumchloride and 0.2 millimolar of a compound of Formula I, thecorresponding non-isotopically enriched compound or standard or controlin 100 millimolar potassium phosphate (pH 7.4) is incubated at 37° C.for 20 min. After incubation, the reaction is stopped by the addition ofan appropriate solvent (e.g. acetonitrile, 20% trichloroacetic acid, 94%acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94%acetonitrile/6% glacial acetic acid) and centrifuged (10,000 g) for 3minutes. The supernatant is analyzed by HPLC/MS/MS.

Cytochrome P₄₅₀ Standard CYP1A2 Phenacetin CYP2A6 Coumarin CYP2B6[¹³C]-(S)-mephenytoin CYP2C8 Paclitaxel CYP2C9 Diclofenac CYP2C19[¹³C]-(S)-mephenytoin CYP2D6 (+/−)-Bufuralol CYP2E1 Chlorzoxazone CYP3A4Testosterone CYP4A [¹³C]-Lauric acid

Example 42—Monoamine Oxidase A Inhibition and Oxidative Turnover

The procedure is carried out as described in Weyler, Journal ofBiological Chemistry 1985, 260, 13199-13207. Monoamine oxidase Aactivity is measured spectrophotometrically by monitoring the increasein absorbance at 314 nm on oxidation of kynuramine with formation of4-hydroxyquinoline. The measurements are carried out, at 30° C., in 50mM NaP, buffer, pH 7.2, containing 0.2% Triton X-100 (monoamine oxidaseassay buffer), plus 1 mM kynuramine, and the desired amount of enzyme in1 mL total volume.

Example 43—Monoamine Oxidase B Inhibition and Oxidative Turnover

The procedure is carried out as described in Uebelhack,Pharmacopsychiatry 1998, 31, 187-192.

Pharmacology

The pharmacological profile of compounds of Formula I or thecorresponding non-isotopically enriched compounds or standards orcontrols can be demonstrated as follows. The preferred exemplifiedcompounds exhibit a K_(i) value less than 1 micromolar, more preferablyless than 500 nanomolar at the Serotonin transporter as determined usingthe scintillation proximity assay (SPA) described below. See WO2005/060949. Furthermore, the preferred exemplified compoundsselectively inhibit the Serotonin transporter relative to theNorepinephrine and dopamine transporters by a factor of at least fiveusing such SPAs.

Example 44—Generation of Stable Cell Lines Expressing the HumanDopamine, Norepinephrine and Serotonin Transporters

Standard molecular cloning techniques are used to generate stablecell-lines expressing the human dopamine, norepinephrine and serotonintransporters. The polymerase chain reaction (PCR) is used in order toisolate and amplify each of the three full-length cDNAs from anappropriate cDNA library. PCR Primers for the following neurotransmittertransporters are designed using published sequence data. The PCRproducts are cloned into a mammalian expression vector, such as forexample pcDNA3.1 (Invitrogen), using standard ligation techniques,followed by co-transfection of HEK293 cells using a commerciallyavailable lipofection reagent (Lipofectamine™—Invitrogen) following themanufacturer's protocol.

-   -   Human Dopamine transporter: GenBank M95167. Vandenbergh et al,        Molecular Brain Research 1992, 15, 161-166, which is hereby        incorporated by reference in its entirety.    -   Human Norepinephrine transporter: GenBank M65105. Pacholczyk et        al, Nature 1991, 350, 350-354, which is hereby incorporated by        reference in its entirety.    -   Human Serotonin transporter: GenBank L05568. Ramamoorthy et al,        Proceedings of the National Academy of Sciences of the USA 1993,        90, 2542-2546, which is hereby incorporated by reference in its        entirety.

Example 45—In Vitro SPA Binding Assay for the Norepinephrine Transporter

The assay is preformed according to the procedure described in Gobel etal, Journal of Pharmacological and Toxicological Methods 1999, 42(4),237-244, which is hereby incorporated by reference in its entirety.Compound of Formula I or the corresponding non-isotopically enrichedcompounds are serotonin/norepinephrine reuptake inhibitors;³H-nisoxetine binding to norepinephrine re-uptake sites in a cell linetransfected with DNA encoding human norepinephrine transporter bindingprotein has been used to determine the affinity of ligands at thenorepinephrine transporter.

Membrane Preparation

Cell pastes from large scale production of HEK-293 cells expressingcloned human norepinephrine transporters are homogenized in 4 volumes of50 millimolar Tris-HCl containing 300 millimolar NaCl and 5 millimolarKCl, pH 7.4. The homogenate is centrifuged twice (40,000 g, 10 minutes,4° C.) with pellet re-suspension in 4 volumes of Tris-HCl buffercontaining the above reagents after the first spin, and 8 volumes afterthe second spin. The suspended homogenate is centrifuged (100 g, 10minutes, 4° C.), the supernatant is kept and re-centrifuged (40,000 g,20 minutes, 4° C.). The pellet is re-suspended in Tris-HCl buffercontaining the above reagents along with 10% w/v sucrose and 0.1millimolar phenylmethylsulfonyl fluoride (PMSF). The membranepreparation is stored in aliquots (1.0 milliliter) at −80° C. untilrequired. The protein concentration of the membrane preparation isdetermined using a Bicinchoninic acid (BCA) protein assay reagent kit(available from Pierce).

[³H]-Nisoxetine Binding Assay

Each well of a 96 well microtiter plate is set up to contain 50microliters of 2 nanomolar [N-methyl-³H]-Nisoxetine hydrochloride (70-87Ci/millimole, from NEN Life Science Products), 75 microliters Assaybuffer (50 millimolar Tris-HCl pH 7.4 containing 300 millimolar NaCl and5 millimolar KCl), 25 microliter of diluted compounds of Formula I orthe corresponding non-isotopically enriched compounds, assay buffer(total binding) or 10 micromolar Desipramine HCl (non-specific binding),50 microliter wheat germ agglutinin coated poly (vinyltoluene) (WGA PVT)SPA Beads (Amersham Biosciences RPNQ0001) (10 milligram/milliliter), 50microliter membrane (0.2 milligram protein per milliliter). Themicrotiter plates are incubated at room temperature for 10 hours priorto reading in a Trilux scintillation counter. The results are analyzedusing an automatic spline-fitting program (Multicalc, Packard, MiltonKeynes, UK) to provide K_(i) values for each of the test compounds.

Example 46—In Vitro SPA Binding Assay for the Serotonin Transporter

The assay is preformed according to the procedure described inRamamoorthy et al, J. Biol. Chem. 1998, 273(4), 2458-2466, which ishereby incorporated by reference in its entirety. The ability of acompound of Formula I or the corresponding non-isotopically enrichedcompound to compete with [³H]-Citalopram for its binding sites on clonedhuman Serotonin transporter containing membranes has been used as ameasure of test compound ability to block Serotonin uptake via itsspecific transporter.

Membrane Preparation

Membrane preparation is essentially similar to that for thenorepinephrine transporter containing membranes as described above. Themembrane preparation is stored in aliquots (1 milliliter) at −70° C.until required. The protein concentration of the membrane preparation isdetermined using a BCA protein assay reagent kit.

[³H]-Citalopram Binding Assay

Each well of a 96 well microtiter plate is set up to contain 50microliters of 2 nanomolar [³H]-citalopram (60-86 Ci/millimole, AmershamBiosciences), 75 microliters Assay buffer (50 millimolar Tris-HCl pH 7.4containing 150 millimolar NaCl and 5 millimolar KCl), 25 microliters ofdiluted compounds of Formula I or the corresponding non-isotopicallyenriched compounds, assay buffer (total binding) or 100 micromolarfluoxetine (non-specific binding), 50 microliters WGA PVT SPA Beads (40milligram/milliliter), 50 microliters membrane preparation (0.4milligram protein per milliliter). The microtiter plates are incubatedat room temperature for 10 hours prior to reading in a Triluxscintillation counter. The results are analyzed using an automaticspline-fitting program (Multicalc, Packard, Milton Keynes, UK) toprovide K_(i) (nanomolar) values for each of the test compounds.

Example 47—In Vitro SPA Binding Assay for the Dopamine Transporter

The assay is preformed according to the procedure described inRamamoorthy et al, J. Biol. Chem. 1998, 273(4), 2458-2466, which ishereby incorporated by reference in its entirety. The ability of a testcompound to compete with [³H]-WIN35,428 for its binding sites on humancell membranes containing cloned human dopamine transporter has beenused as a measure of the ability of such test compounds to blockdopamine uptake via its specific transporter.

Membrane Preparation

Membrane preparation is performed in the same manner as membranescontaining cloned human Serotonin transporter as described above.

[³H]-WIN35,428 Binding Assay

Each well of a 96 well microtiter plate is set up to contain 50microliters of 4 nanomolar [³H]-WIN35,428 (84-87 Ci/millimole, from NENLife Science Products), 5 microliters Assay buffer (50 millimolarTris-HCl pH 7.4 containing 150 millimolar NaCl and 5 millimolar KCl), 25microliters of diluted compounds of Formula I or the correspondingnon-isotopically enriched compounds, assay buffer (total binding) or 100micromolar nomifensine (non-specific binding), 50 microliters WGA PVTSPA Beads (10 milligram/milliliter), 50 microliters membrane preparation(0.2 milligram protein per milliliter). The microtiter plates areincubated at room temperature for 120 minutes prior to reading in aTrilux scintillation counter. The results are analyzed using anautomatic spline-fitting program (Multicalc, Packard, Milton Keynes, UK)to provide K_(i) values for each of the test compounds.

Example 48—In Vivo Assay for Behavioral Despair in Rats

The assay is performed according to the procedure described in Porsoltet al, Archives Internationales de Pharmacodynamie et de Therapie, 1977,229(2), 327-336, which is hereby incorporated by reference in itsentirety. After intraperitoneal administration of test compound in rats,animals are put in a cylinder containing water for 6 minutes. Immobilitytime is measured during the last 4 minutes. Diminished time ofimmobility is indicative of increased efficacy.

The examples set forth above are disclosed to give a complete disclosureand description of how to make and use the claimed embodiments, and arenot intended to limit the scope of what is disclosed herein.Modifications that are obvious, are intended to be within the scope ofthe following claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.However, with respect to any similar or identical terms found in boththe incorporated publications, references, patent or patent applicationsand those explicitly put forth or defined in this document, then thoseterms definitions or meanings explicitly put forth in this documentshall control in all respects.

REFERENCES CITED

The disclosures of each of the following references are incorporated byreference herein in their entireties.

Patent Documents

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1. Polymorph Form B of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine hydrochloride) having the structural formula:


2. The Polymorph Form B of claim 1, wherein each position designed as D has a deuterium enrichment of no less than 5% above the naturally occurring distribution of deuterium.
 3. The Polymorph Form B of claim 1, wherein each position designed as D has a deuterium enrichment of no less than 10% above the naturally occurring distribution of deuterium.
 4. The Polymorph Form B of claim 1, wherein each position designed as D has a deuterium enrichment of no less than 20% above the naturally occurring distribution of deuterium.
 5. The Polymorph Form B of claim 1, wherein each position designed as D has a deuterium enrichment of no less than 50% above the naturally occurring distribution of deuterium.
 6. The Polymorph Form B of claim 1, wherein each position designed as D has a deuterium enrichment of no less than 70% above the naturally occurring distribution of deuterium.
 7. The Polymorph Form B of claim 1, wherein each position designed as D has a deuterium enrichment of no less than 80% above the naturally occurring distribution of deuterium.
 8. The Polymorph Form B of claim 1, wherein each position designed as D has a deuterium enrichment of no less than 90% above the naturally occurring distribution of deuterium.
 9. The Polymorph Form B of claim 1, wherein each position designed as D has a deuterium enrichment of no less than 98% above the naturally occurring distribution of deuterium.
 10. A pharmaceutical composition comprising the compound as recited in claim 1 and one or more pharmaceutically acceptable carriers.
 11. The pharmaceutical composition as recited in claim 10, further comprising one or more release-controlling carriers.
 12. The pharmaceutical composition as recited in claim 10, further comprising one or more non-release controlling carriers.
 13. The pharmaceutical composition as recited in claim 10, wherein the composition is suitable for oral, parenteral, or intravenous infusion administration.
 14. The pharmaceutical composition as recited in claim 10, wherein the oral dosage form is a tablet or capsule.
 15. The pharmaceutical composition as recited in claim 10, wherein the compound is administered in a dose of about 0.5 milligrams to about 1,000 milligrams. 